Macrocyclic complexes of radionuclides and their use in radiotherapy of cancer

Abstract

Formulas Z³ O O N N N O N O O OH z¹ Z² W Z³ N M N N O N O OH ZZ² W O N M N N O N O O OH 5 L R 26 20 26 24 90 88 09 O ct 2 02 6 A B S T R A C T 2 0 2 6 2 4 9 0 8 8 0 9 O c t 2 0 2 6 F o r m u l a s O O N N N O N O O O H 1 W N M N N O N O H Z W O N M N N O N O O H L R 2 6

Description

[0108] The tripartite compounds of the present technology include variations on any of the three domains: e.g., the domain including the chelator, the domain including the albuminbinding group, or the domain including the tumor targeting moiety. The following are exemplary.

[0109] RPS-092. / —N 0 ) VoH d “ HN >s HN                  a- ;  _.o ° q >4 ANH O O—2 O HN CO2H     A        Nn \n ho2c n n co2h H H In any embodiment disclosed herein, RPS-92 may optionally chelate 213Bi3+, 211At+,' 212Pb2+ , or 212Pb4+. y                           HNA .r^ O N^              HN^ ) Vn O                CO2H o-2 d W        o-' o 7    ^=7 OH      / —2 >25Ac3+; 152Dy3+) 212Bi3+ 211^3+ 217^+, 227^4+ 226^4+ 233^2+

[0110] NTI-093 is an analog of NTI-063, where TCMC is used as the chelator. In any embodiment disclosed herein, NTI-93 may optionally chelate 212Pb2+ or 212Pb4+.

[0111] NTI-094 is an analog of NTI-072, where TCMC is used as the chelator. In any embodiment disclosed herein, NTI-94 may optionally chelate 212Pb2+ or 212Pb4+.

[0112] The following is a Bromo analog of NTI-063, with modification to the albumin binding domain. HN

[0113] The following is a Chloro analog of NTI-063, with modification to the albumin binding domain.

[0114] NTI-309 modifies the tumor targeting domain, to target seprase (Fibroblast Activation Protein / FAP).

[0115] The NTI-309 compound can be include TCMC as the chelator. In any embodiment disclosed herein, NTI-309 may optionally chelate 212Pb2+ or 212Pb4+.

[0116] The following is a Boronic acid analog of NTI-309. \ OH

[0117] The following is a Boronic acid analog of NTI-309, using TCMC as a chelator. In any embodiment disclosed herein, this analog may optionally chelate 212Pb2+ or 212Pb4+.

[0118] Further by way of specific examples, a derivative of RPS-072 (which itself targets PSMA), can be constructed, where TTT has affinity for the SSTR2 receptor, using a derivative of lanreotide where this compound (A) has a molecular weight of 3537.93 and a formula of C165H235IN28O44S3. Similarly, a derivative of RPS-072 can be prepared, that targets GRP / bombesin receptor, where this compound (B) has a molecular weight of 3537.93 and a formula of C167H248IN31O44S. (A) H (B) 2026249088  09 Oct 2026

[0119] The present technology also provides compositions (e.g., pharmaceutical compositions) and medicaments comprising any of one of the embodiments of the compounds of Formulas I, IA, II, any one of the modified antibodies, modified antibody fragments, or modified binding peptides of the present technology disclosed herein, or any one of the embodiments of the tripartite compounds disclosed herein and a pharmaceutically acceptable carrier or one or more excipients or fillers (collectively refered to as “pharmaceutically acceptable carrier” unless otherwise specified). The compositions may be used in the methods and treatments described herein. The pharmaceutical composition may include an effective amount of any embodiment of the compounds of the present technology for treating the cancer and / or mammalian tissue overexpressing PSMA or an effective amount of any embodiment of the modified antibody, modified antibody fragment, or modified binding peptide of the present technology for treating the cancer and / or mammalian tissue overexpressing PSMA or an effective amount of any embodiment of the tripartite compound of the present technology for treating the cancer and / or mammalian tissue overexpressing PSMA. In an related aspect, a method of treating a subject is provided, wherein the method includes administering a targeting compound of the present technology to the subject or administering a modified antibody, modified antibody fragment, or modified binding peptide of the present technology to the subject. In any embodiment disclosed herein, it may be that the subject suffers from cancer and / or mammalian tissue overexpressing prostate specific membrane antigen (“PSMA”). In any embodiment herein, it may be the administering includes administering an effective amount of any embodiment of the compounds of the present technology for treating the cancer and / or mammalian tissue overexpressing PSMA of the compound or an effective amount of any embodiment of the modified antibody, modified antibody fragment, or modified binding peptide of the present technology for treating the cancer and / or mammalian tissue overexpressing PSMA or an effective amount of any embodiment of the tripartite compound of the present technology for treating the cancer and / or mammalian tissue overexpressing PSMA. The subject may suffer from a mammalian tissue expressing a somatostatin receptor, a bombesin receptor, seprase, or a combination of any two or more thereof and / or mammalian tissue overexpressing PSMA. The mammalian tissue of any embodiment disclosed herein may include one or more of a growth hormone producing tumor, a neuroendocrine tumor, a pituitary tumor, a vasoactive intestinal peptide-secreting tumor, a small cell carcinoma of the lung, gastric cancer tissue, pancreatic cancer tissue, a neuroblastoma, and a metastatic cancer. In any embodiment disclosed herein, the subject may suffer from one or more of a glioma, a breast cancer, an adrenal cortical cancer, a cervical carcinoma, a vulvar carcinoma, an endometrial carcinoma, a primary ovarian carcinoma, a metastatic ovarian carcinoma, a non-small cell lung cancer, a small cell lung cancer, a bladder cancer, a colon 2026249088  09 Oct 2026 cancer, a primary gastric adenocarcinoma, a primary colorectal adenocarcinoma, a renal cell carcinoma, and a prostate cancer. In any embodiment disclosed herein, the composition (e.g., pharmaceutical composition) and / or medicament may be formulated for parenteral administration. In any embodiment disclosed herein, the composition (e.g., pharmaceutical composition) and / or medicament may be formulated for intraveneous administration. In any embodiment disclosed herein, the administering step of the method may include parenteral administration. In any embodiment disclosed herein, the administering step of the method may include intraveneous administration.

[0120] In any of the above embodiments, the effective amount may be determined in relation to a subject. “Effective amount” refers to the amount of a compound or composition required to produce a desired effect. One non-limiting example of an effective amount includes amounts or dosages that yield acceptable toxicity and bioavailability levels for therapeutic (pharmaceutical) use including, but not limited to, the treatment of e.g., one or more of a glioma, a breast cancer, an adrenal cortical cancer, a cervical carcinoma, a vulvar carcinoma, an endometrial carcinoma, a primary ovarian carcinoma, a metastatic ovarian carcinoma, a non-small cell lung cancer, a small cell lung cancer, a bladder cancer, a colon cancer, a primary gastric adenocarcinoma, a primary colorectal adenocarcinoma, a renal cell carcinoma, and a prostate cancer. Another example of an effective amount includes amounts or dosages that are capable of reducing symptoms associated with e.g., one or more of a glioma, a breast cancer, an adrenal cortical cancer, a cervical carcinoma, a vulvar carcinoma, an endometrial carcinoma, a primary ovarian carcinoma, a metastatic ovarian carcinoma, a non-small cell lung cancer, a small cell lung cancer, a bladder cancer, a colon cancer, a primary gastric adenocarcinoma, a primary colorectal adenocarcinoma, a renal cell carcinoma, and a prostate cancer, such as, for example, reduction in proliferation and / or metastasis of prostate cancer, breast cancer, or bladder cancer.. The effective amount may be from about 0.01 pg to about 1 mg of the compound per gram of the composition, and preferably from about 0.1 pg to about 500 pg of the compound per gram of the composition. As used herein, a “subject” or “patient” is a mammal, such as a cat, dog, rodent or primate. Typically the subject is a human, and, preferably, a human suffering from or suspected of suffering from one or more of a glioma, a breast cancer, an adrenal cortical cancer, a cervical carcinoma, a vulvar carcinoma, an endometrial carcinoma, a primary ovarian carcinoma, a metastatic ovarian carcinoma, a non-small cell lung cancer, a small cell lung cancer, a bladder cancer, a colon cancer (such as colon adenocarcinoma), a primary gastric adenocarcinoma, a primary colorectal adenocarcinoma, a renal cell carcinoma, and a prostate cancer. The term “subject” and “patient” can be used interchangeably. 2026249088  09 Oct 2026

[0121] In any of the embodiments of the present technology described herein, the pharmaceutical composition may be packaged in unit dosage form. The unit dosage form is effective in treating one or more of a glioma, a breast cancer, an adrenal cortical cancer, a cervical carcinoma, a vulvar carcinoma, an endometrial carcinoma, a primary ovarian carcinoma, a metastatic ovarian carcinoma, a non-small cell lung cancer, a small cell lung cancer, a bladder cancer, a colon cancer (such as colon adenocarcinoma), a primary gastric adenocarcinoma, a primary colorectal adenocarcinoma, a renal cell carcinoma, and a prostate cancer. Generally, a unit dosage including a compound of the present technology will vary depending on patient considerations. Such considerations include, for example, age, protocol, condition, sex, extent of disease, contraindications, concomitant therapies and the like. An exemplary unit dosage based on these considerations may also be adjusted or modified by a physician skilled in the art. For example, a unit dosage for a patient comprising a compound of the present technology may vary from 1 x 10-4g / kg to 1 g / kg, preferably, 1 x 10-3 g / kg to 1.0 g / kg. Dosage of a compound of the present technology may also vary from 0.01 mg / kg to 100 mg / kg or, preferably, from 0.1 mg / kg to 10 mg / kg. Suitable unit dosage forms, include, but are not limited to powders, tablets, pills, capsules, lozenges. suppositories. patches. nasal sprays, injectibles, implantable sustained-release formulations, rnucoadherent films, topical varnishes, lipid complexes, etc.

[0122] The pharmaceutical compositions may be prepared by mixing one or more of the compounds of Formulas I, IA, II, or any one of the modified antibodies, modified antibody fragments, or modified binding peptides of the present technology, or any embodiment of the tripartite compound of the present technology, pharmaceutically acceptable salts thereof, stereoisomers thereof, tautomers thereof, or solvates thereof, with pharmaceutically acceptable carriers, excipients, binders, diluents or the like to prevent and treat disorders associated with cancer and / or a mammalian tissue overexpressing PSMA. The compounds and compositions described herein may be used to prepare formulations and medicaments that treat e.g., prostate cancer, breast cancer, or bladder cancer. Such compositions may be in the form of, for example, granules, powders, tablets, capsules, syrup, suppositories, injections, emulsions, elixirs, suspensions or solutions. The instant compositions may be formulated for various routes of administration, for example, by oral, parenteral, topical, rectal, nasal, vaginal administration, or via implanted reservoir. Parenteral or systemic administration includes, but is not limited to, subcutaneous, intravenous, intraperitoneal, and intramuscular, injections. The following dosage forms are given by way of example and should not be construed as limiting the instant present technology. 2026249088  09 Oct 2026

[0123] For oral, buccal, and sublingual administration, powders, suspensions, granules, tablets, pills, capsules, gelcaps, and caplets are acceptable as solid dosage forms. These can be prepared, for example, by mixing one or more compounds of the instant present technology, or pharmaceutically acceptable salts or tautomers thereof, with at least one additive such as a starch or other additive. Suitable additives are sucrose, lactose, cellulose sugar, mannitol, maltitol, dextran, starch, agar, alginates, chitins, chitosans, pectins, tragacanth gum, gum arabic, gelatins, collagens, casein, albumin, synthetic or semi-synthetic polymers or glycerides. Optionally, oral dosage forms can contain other ingredients to aid in administration, such as an inactive diluent, or lubricants such as magnesium stearate, or preservatives such as paraben or sorbic acid, or anti-oxidants such as ascorbic acid, tocopherol or cysteine, a disintegrating agent, binders, thickeners, buffers, sweeteners, flavoring agents or perfuming agents. Tablets and pills may be further treated with suitable coating materials known in the art.

[0124] Liquid dosage forms for oral administration may be in the form of pharmaceutically acceptable emulsions, syrups, elixirs, suspensions, and solutions, which may contain an inactive diluent, such as water. Pharmaceutical formulations and medicaments may be prepared as liquid suspensions or solutions using a sterile liquid, such as, but not limited to, an oil, water, an alcohol, and combinations of these. Pharmaceutically suitable surfactants, suspending agents, emulsifying agents, may be added for oral or parenteral administration.

[0125] As noted above, suspensions may include oils. Such oils include, but are not limited to, peanut oil, sesame oil, cottonseed oil, corn oil and olive oil. Suspension preparation may also contain esters of fatty acids such as ethyl oleate, isopropyl myristate, fatty acid glycerides and acetylated fatty acid glycerides. Suspension formulations may include alcohols, such as, but not limited to, ethanol, isopropyl alcohol, hexadecyl alcohol, glycerol and propylene glycol. Ethers, such as but not limited to, poly(ethyleneglycol), petroleum hydrocarbons such as mineral oil and petrolatum; and water may also be used in suspension formulations.

[0126] Injectable dosage forms generally include aqueous suspensions or oil suspensions which may be prepared using a suitable dispersant or wetting agent and a suspending agent. Injectable forms may be in solution phase or in the form of a suspension, which is prepared with a solvent or diluent. Acceptable solvents or vehicles include sterilized water, Ringer's solution, or an isotonic aqueous saline solution. Alternatively, sterile oils may be employed as solvents or suspending agents. Typically, the oil or fatty acid is non-volatile, including natural or synthetic oils, fatty acids, mono-, di- or tri-glycerides. 2026249088  09 Oct 2026

[0127] For injection, the pharmaceutical formulation and / or medicament may be a powder suitable for reconstitution with an appropriate solution as described above. Examples of these include, but are not limited to, freeze dried, rotary dried or spray dried powders, amorphous powders, granules, precipitates, or particulates. For injection, the formulations may optionally contain stabilizers, pH modifiers, surfactants, bioavailability modifiers and combinations of these.

[0128] Compounds of the present technology may be administered to the lungs by inhalation through the nose or mouth. Suitable pharmaceutical formulations for inhalation include solutions, sprays, dry powders, or aerosols containing any appropriate solvents and optionally other compounds such as, but not limited to, stabilizers, antimicrobial agents, antioxidants, pH modifiers, surfactants, bioavailability modifiers and combinations of these. The carriers and stabilizers vary with the requirements of the particular compound, but typically include nonionic surfactants (Tweens, Pluronics, or polyethylene glycol), innocuous proteins like serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars or sugar alcohols. Aqueous and nonaqueous (e.g., in a fluorocarbon propellant) aerosols are typically used for delivery of compounds of the present technology by inhalation.

[0129] Besides those representative dosage forms described above, pharmaceutically acceptable excipients and carriers are generally known to those skilled in the art and are thus included in the instant present technology. Such excipients and carriers are described, for example, in “Remingtons Pharmaceutical Sciences” Mack Pub. Co., New Jersey (1991), which is incorporated herein by reference. The instant compositions may also include, for example, micelles or liposomes, or some other encapsulated form.

[0130] Specific dosages may be adjusted depending on conditions of disease, the age, body weight, general health conditions, sex, and diet of the subject, dose intervals, administration routes, excretion rate, and combinations of drugs. Any of the above dosage forms containing effective amounts are well within the bounds of routine experimentation and therefore, well within the scope of the instant present technology.

[0131] Various assays and model systems can be readily employed to determine the therapeutic effectiveness of the treatment according to the present technology.

[0132] For the indicated condition, test subjects will exhibit a 10%, 20%, 30%, 50% or greater reduction, up to a 75-90%, or 95% or greater, reduction, in one or more symptom(s) caused by, or associated with, the disorder in the subject, compared to placebo-treated or other suitable control subjects. 2026249088  09 Oct 2026

[0133] In another aspect, the present technology provides a method of treating cancer by administering an effective amount of the targeting composition according to Formula II to a subject having cancer. Since a cancer cell targeting agent can be selected to target any of a wide variety of cancers, the cancer considered herein for treatment is not limited. The cancer can be essentially any type of cancer. For example, antibodies or peptide vectors can be produced to target any of a wide variety of cancers. The targeting compositions described herein are typically administered by injection into the bloodstream, but other modes of administration, such as oral or topical administration, are also considered. In some embodiments, the targeting composition may be administered locally, at the site where the target cells are present, i.e., in a specific tissue, organ, or fluid (e.g., blood, cerebrospinal fluid, etc.). Any cancer that can be targeted through the bloodstream is of particular consideration herein. Some examples of applicable body parts containing cancer cells include the breasts, lungs, stomach, intestines, prostate, ovaries, cervix, pancreas, kidney, liver, skin, lymphs, bones, bladder, uterus, colon, rectum, and brain. The cancer can also include the presence of one or more carcinomas, sarcomas, lymphomas, blastomas, or teratomas (germ cell tumors). The cancer may also be a form of leukemia. In some embodiments, the cancer is a triple negative breast cancer.

[0134] As is well known in the art, the dosage of the active ingredient(s) generally depends on the disorder or condition being treated, the extent of the disorder or condition, the method of administration, size of the patient, and potential side effects. In different embodiments, depending on these and other factors, a suitable dosage of the targeting composition may be precisely, at least, above, up to, or less than, for example, 1 mg, 10 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1200 mg, or 1500 mg, or a dosage within a range bounded by any of the foregoing exemplary dosages. Furthermore, the composition can be administered in the indicated amount by any suitable schedule, e.g., once, twice, or three times a day or on alternate days for a total treatment time of one, two, three, four, or five days, or one, two, three, or four weeks, or one, two, three, four, five, or six months, or within a time frame therebetween. Alternatively, or in addition, the composition can be administered until a desired change in the disorder or condition is realized, or when a preventative effect is believed to be provided.

[0135] The examples herein are provided to illustrate advantages of the present technology and to further assist a person of ordinary skill in the art with preparing or using the compounds of the present technology or salts, pharmaceutical compositions, derivatives, prodrugs, or tautomeric forms thereof. The examples herein are also presented in order to more fully 2026249088  09 Oct 2026 illustrate the preferred aspects of the present technology. The examples should in no way be construed as limiting the scope of the present technology, as defined by the appended claims. The examples can include or incorporate any of the variations, aspects or embodiments of the present technology described above. The variations, aspects or embodiments described above may also further each include or incorporate the variations of any or all other variations, aspects or embodiments of the present technology. EXAMPLES

[0136] Exemplary Synthetic Procedures and Characterization

[0137] Materials and Instrumentation. All solvents and reagents, unless otherwise noted, were purchased from commercial sources and used as received without further purification. Solvents noted as “dry” were obtained following storage over 3 A molecular sieves. Metal salts were purchased from Strem Chemicals (Newburyport, MA) and were of the highest purity available; Lu(ClO4)3 was provided as an aqueous solution containing 15.1 wt% Lu. The bifunctional ligand p-SCN-Bn-DOTA was purchased from Macrocyclics (Plano, TX). NMe4OH was purchased as a 25 wt% solution in H2O (trace metals basis, Beantown Chemical, Hudson, NH). Hydrochloric acid (BDH Aristar Plus, VWR, Radnor, PA) and nitric acid (Optima, ThermoFisher Scientific, Waltham, MA) were of trace metals grade. Both Chelex 100 (sodium form, 50-100 mesh) and human serum used for 225Ac-complex challenge assays were purchased from Sigma Aldrich (St. Louis, MO). Deionized water (>18 MQ cm) was prepared on site using either Millipore Direct-Q® 3UV or Elga Purelab Flex 2 water purification systems.

[0138] Reactions were monitored by thin-layer chromatography (TLC, Whatman UV254 aluminum-backed silica gel). The HPLC system used for analysis and purification of compounds consisted of a CBM-20A communications bus module, an LC-20AP (preparative) or LC-20AT (analytical) pump, and an SPD-20AV UV / Vis detector monitoring at 270 nm (Shimadzu, Japan). Analytical chromatography was carried out using an Ultra Aqueous C18 column, 100 A, 5 ^m, 250 mm x 4.6 mm (Restek, Bellefonte, PA) at a flow rate of 1.0 mL / min, unless otherwise noted. Purification was performed with an Epic Polar preparative column, 120 A, 10 ^m, 25 cm x 20 mm (ES Industries, West Berlin, NJ) at a flow rate of 14 mL / min, unless otherwise noted. Gradient HPLC methods were employed using a binary mobile phase that contained H2O (A) and either MeOH (B) or ACN (C). HPLC Method A: 10% B (0-5 min), 10100% B (5-25 min). Method B: 10% C (0-5 min), 10-100% C (5-25 min). Method C: 10% C (0-5 min), 10-100% C (5-40 min). Method D: 10% C (0-5 min), 10-100% C (5-20 min). The solvent systems contained 0.1% trifluoroacetic acid (TFA), except for Method C, in which 0.2% 2026249088  09 Oct 2026 TFA was used. NMR spectra were recorded at ambient temperature on Varian Inova 300 MHz, 400 MHz, 500 MHz or 600 MHz spectrometers, or on a Bruker AV III HD 500 MHz spectrometer equipped with a broadband Prodigy cryoprobe. Chemical shifts are reported in ppm. 1H and 13C NMR spectra were referenced to the TMS internal standard (0 ppm), to the residual solvent peak, or to an acetonitrile internal standard (2.06 ppm in D2O spectra). 19F NMR spectra were referenced to a monofluorobenzene internal standard (-113.15 ppm). The splitting of proton resonances in the reported 1H spectra is defined as: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, dt = doublet of triplets, td = triplet of doublets, and br = broad. IR spectroscopy was performed on a KBr pellet of sample using a Nicolet Avatar 370 DTGS (ThermoFisher Scientific, Waltham, MA). High-resolution mass spectra (HRMS) were recorded on an Exactive Orbitrap mass spectrometer in positive ESI mode (ThermoFisher Scientific, Waltham, MA). UV / visible spectra were recorded on a Cary 8454 UV-Vis (Agilent Technologies, Santa Clara, CA) using 1-cm quartz cuvettes, unless otherwise noted. Elemental analysis (EA) was performed by Atlantic Microlab, Inc. (Norcross, GA).

[0139] Synthesis and Characterization of Macropa Complexes, Macropa-NCS, and Macropa-NHC(S)NHCH3. N, N‘-bis[(6-carboxy-2-pyridil)methyl]-4,13-diaza-18-crown-6 (H2macropa- 2HCl • 4H2O)[102’103] was prepared using 1,7,10,16-tetraoxa-4,13-diazacyclooctadecane (7) that was either purchased from EMD Millipore (Darmstadt, Germany) or synthesized via literature protocols.

[104] Chelidamic acid monohydrate (1) was purchased from TCI America (Portland, OR). Dimethyl 4-chloropyridine-2,6-dicarboxylate (2),

[105] dimethyl 4-azidopyridine- 2,6-dicarboxylate (3),

[106] and 6-chloromethylpyridine-2-carboxylic acid methyl ester (8),

[102] were prepared via the indicated literature protocols.

[0140] Preparation of [La(macropa)]2+. To a suspension of H2macropa-2HCl-4H2O (0.0233 g, 0.034 mmol) in 2-propanol (0.6 mL) was added triethylamine (20 pL, 0.143 mmol). The pale-gold solution was heated at reflux for 25 min before a solution of La(ClO4)3’6H2O (0.0209 g, 0.038 mmol) in 2-propanol (0.5 mL) was added dropwise. A precipitate formed immediately. The cream suspension was stirred at reflux 2026249088  09 Oct 2026 for an additional 1.5 h before it was cooled and centrifuged. The supernatant was removed, and the pellet was washed with 2-propanol (2 x 1 mL) and then air-dried on filter paper to give the title complex as a pale-tan solid (0.0177 g) containing 0.64 equiv of 2-propanol. 1H NMR (500 MHz, D2O, pD - 9) 8= 7.87 (t, J = 7.8 Hz, 2H), 7.54 (d, J = 7.8 Hz, 2H), 7.39 (d, J = 7.6 Hz, 2H), 5.21 (d, J = 15.7 Hz, 2H), 4.44 (t, J = 11.6 Hz, 2H), 4.09 (t, J = 11.2 Hz, 4H), 4.01 (t, J = 10.4 Hz, 2H), 3.74 (d, J = 9.9 Hz, 2H), 3.65-3.60 (m, 4H), 3.58-3.47 (m, 4H), 3.44 (d, J = 10.8 Hz, 2H), 2.75 (td, J = 13.1, 2.7 Hz, 2H), 2.56 (d, J = 13.9 Hz, 2H), 2.38 (d, J = 14.0 Hz, 2H). 13C{1H} APT NMR (126 MHz, D2O, pD - 9) 8= 172.62, 158.70, 150.19, 140.94, 126.89, 122.32, 71.88, 70.12, 69.20, 68.05, 60.14, 56.08, 54.01. EA Found: C, 35.16; H, 4.73; N, 5.91. Calc. for C26H35LaN4O8-2ClO4-2H2O-0.64iPrOH: C, 35.53; H, 4.71; N, 5.94. IR (cm-1): 3443, 2913, 1630, 1596, 1461, 1370, 1265, 1083, 948, 839, 770, 678, 617, 513. HPLC tr = 18.104 min (Method A). HRMS (m / z): 669.14289, 335.07519; Calc for [C26H34LaN4O8]+ and [C26H35LaN4O8]2+, respectively: 669.14346, 335.07537.

[0141] Preparation of [Lu(macropa)]+. To a suspension H2macropa-2HCl-4H2O (0.0730 g, 0.108 mmol) in 2-propanol (2 mL) was added triethylamine (61.5 pL, 0.441 mmol). The pale-gold solution was heated at reflux for 25 min before a solution of aq. Lu(ClO4)3 (0.1372 g, 0.118 mmol Lu) in 2-propanol (1.8 mL) was added dropwise. A precipitate formed immediately. After stirring at reflux or an additional 1 h, the cream suspension was triturated at RT for 20 h and then centrifuged. The supernatant was removed, and the pellet was washed with 2-propanol (2 x 2 mL) and then air-dried on filter paper to give the title complex as a pale-tan solid (0.0605 g) containing residual 2-propanol and triethylamine salt. 1H NMR (600 MHz, D2O, pD - 7-8) 8= 7.85 (t, J = 7.7 Hz, 2H), 7.52 (d, J = 7.8 Hz, 2H), 7.37 (d, J = 7.6 Hz, 2H), 4.68 (d, J = 16.3 Hz, 2H), 4.56 (td, J = 11.2, 1.7 Hz, 2H), 4.42-4.38 (m, 2H), 4.23-4.19 (m, 6H), 4.07 (d, J = 16.3 Hz, 2H), 3.96-3.87 (m, 2H), 3.71-3.63 (m, 4H), 3.38 (td, J = 10.0, 4.7 Hz, 2H), 3.00 (m, 2H), 2.93 (d, J = 13.1 Hz, 2H), 2.52 (dt, J = 14.8, 4.5 Hz, 2H). 13C{1H} APT NMR (126 MHz, D2O, pD - 7-8) 8= 172.13, 158.67, 148.98, 141.81, 127.38, 122.83, 75.33, 73.12, 71.97, 71.70, 64.65, 57.37, 55.08. IR (cm-1): 3400, 1639, 2026249088  09 Oct 2026 1396, 1274, 1091, 913, 770, 678, 622. HPLC tr = not stable (Method A). HRMS (m / z): 705.17772; Calc for [C26H34LuN4O8]+: 705.17788.

[0142] Preparation of dimethyl 4-aminopyridine-2,6-dicarboxylate (4). Dimethyl 4-azidopyridine-2,6-dicarboxylate (3, 0.9445 g, 4.0 mmol), 10% Pd / C (0.1419 g), and DCM:MeOH (1:1, 18 mL) were combined in a round-bottom flask. After purging the flask with a balloon of H2, the reaction was stirred vigorously at room temperature under an H2 atmosphere for 46 h. The gray mixture was diluted with DMF (450 mL) and filtered through a bed of Celite. Following a subsequent filtration through a 0.22 pm nylon membrane, the filtrate was concentrated at 60 °C under reduced pressure and further dried in vacuo to obtain 4 as a pale-tan solid (0.824 g, 98% yield). 1H NMR (500 MHz, DMSO-d6): 8= 7.36 (s, 2 H), 6.72 (s, 2 H), 3.84 (s, 6 H). 13C{1H} APT NMR (126 MHz, DMSO-d6): 8= 165.51, 156.24, 148.05, 111.99, 52.29. IR (cm-1): 3409, 3339, 3230, 1726, 1639, 1591, 1443, 1265, 996, 939, 787, 630, 543. HPLC tR = 9.369 min (Method B). HRMS (m / z): 211.07213 [M + H]+; Calc: 211.07133.

[0143] Preparation of Ethyl 4-amino-6-(hydroxymethyl)picolinate (5). To a refluxing suspension of 4 (0.677 g, 3.22 mmol) in absolute EtOH (27 mL) was added NaBH4 (0.1745 g, 4.61 mmol) portionwise over 1 h to give a pale-yellow suspension. The reaction was then quenched with acetone (32 mL) and concentrated at 60 °C under reduced pressure to a tan solid. The crude product was dissolved in H2O (60 mL) and washed with ethyl acetate (4 x 150 mL). The combined organics were dried over sodium sulfate and concentrated at 40 °C under reduced pressure. Further drying in vacuo yielded 5 as a pale-yellow solid (0.310 g, 49% yield). 1H NMR (300 MHz, DMSO-d6): 8= 7.07 (d, J = 2.1 Hz, 1H), 6.78 (m, 1H), 6.32 (s, 2H), 5.30 (t, J = 5.8 Hz, 1H), 4.39 (d, J = 5.6 Hz, 2H), 4.26 (q, J = 7.1 Hz, 2H), 1.28 (t, J = 2026249088  09 Oct 2026 7.1 Hz, 3H). 13C APT NMR (126 MHz, DMSO-d6) 8= 165.57, 162.38, 155.68, 147.25, 108.50, 107.01, 63.95, 60.61, 14.24. IR (cm-1): 3439, 3217, 2974, 2917, 1717, 1643, 1600, 1465, 1396, 1378, 1239, 1135, 1022, 974, 865, 783. HPLC tr = 8.461 min (Method B). HRMS (m / z): 197.09288 [M + H]+; Calc: 197.09207.

[0144] Preparation of Ethyl 4-amino-6-(chloromethyl)picolinate (6). A mixture of thionyl chloride (2.5 mL) and 5 (0.301 g, 1.53 mmol) was stirred in an ice bath for 1 h, and then at RT for 30 min. The yellow-orange emulsion was concentrated at 40 °C under reduced pressure to an oily residue. The residue was neutralized with sat. aq. NaHCO3 (12 mL) and then extracted with ethyl acetate (75 mL). The organic extract was washed with H2O (2 mL), dried over sodium sulfate, and concentrated at 40 °C under reduced pressure. Further drying in vacuo gave 6 as an amber wax (0.287 g, 80% yield, corrected for residual ethyl acetate). 1H NMR (500 MHz, DMSO-d6) 8= 7.18 (d, J = 2.1 Hz, 1H), 6.78 (d, J = 2.1 Hz, 1H), 6.62 (br s, 2H), 4.62 (s, 2H), 4.29 (q, J = 7.1 Hz, 2H), 1.30 (t, J = 7.1 Hz, 3H). 13C{1H} APT NMR (126 MHz, DMSO-d6) 8= 164.75, 156.42, 156.19, 147.17, 109.79, 109.50, 60.97, 46.47, 14.15. IR (cm-1): 3452, 3322, 3209, 2978, 2922, 1726, 1639, 1604, 1513, 1465, 1378, 1248, 1126, 1026, 983, 861, 783, 752, 700. HPLC tr = 12.364 min (Method B). HRMS (m / z): 215.05903 [M + H]+; Calc: 215.05818.

[0145] Preparation of Methyl 6-((1,4,10,13-tetraoxa-7,16-diazacyclooctadecan-7-yl)methyl)picolinate (9-2TFA-1H2O). To a clear and colorless solution of 1,7,10,16-tetraoxa-4,13-diazacyclooctadecane (7, 1.9688 g, 7.5 mmol) and diisopropylethylamine (0.8354 g, 6.5 mmol) in dry ACN (1.075 L) at 75 °C was 2026249088  09 Oct 2026 added dropwise a solution of 6 (0.9255 g, 5.0 mmol) in dry ACN (125 mL) over 2 h 40 min. The flask was then equipped with a condenser and drying tube, and the slightly-yellow solution was heated at reflux for 42 h. Subsequently, the dark-gold solution containing fine, white precipitate was concentrated at 60 °C under reduced pressure to an amber oil. To the crude oil was added 10% MeOH / H2O containing 0.1% TFA (10 mL). The slight suspension was filtered, and the filtrate was purified by preparative HPLC (Method A). Pure fractions were combined, concentrated at 60 °C under reduced pressure, and then lyophilized to give 9 (1.6350 g, 50% yield) as a pale-orange solid. 1H NMR (500 MHz, DMSO-d6) 8= 8.75 (br s, 2H), 8.17-8.06 (m, 2H), 7.83 (dd, J = 7.4, 1.5 Hz, 1H), 4.68 (br s, 2H), 3.91 (s, 3H), 3.85 (br t, J = 5.1 Hz, 4H), 3.69 (t, J = 5.1 Hz, 4H), 3.59 (br s, 8H), 3.50 (br s, 4H), 3.23 (br t, J = 5.1 Hz, 4H). 13C{1H} APT NMR (126 MHz, DMSO-d6) 8 164.68, 158.78-157.98 (q, TFA), 151.44, 147.13, 139.01, 128.63, 124.87, 120.08-113.01 (q, TFA), 69.33, 69.00, 65.31, 64.60, 56.43, 53.29, 52.67, 46.32. 19F NMR (470 MHz, DMSO-d6) 8= -73.84. EA Found: C, 43.88; H, 5.29; N, 6.28. Calc. for C20H33N3O6-2CF3COOH- IH2O: C, 43.84; H, 5.67; N, 6.39. HPLC tR = 12.372 min (Method B). HRMS (m / z): 412.24568 [M + H]+; Calc: 412.24421.

[0146] Preparation of Ethyl 4-amino-6-((16-((6-(methoxycarbonyl)pyridin-2-yl)methyl)-1,4,10,13-tetraoxa- 7,16-diazacyclooctadecan-7-yl)methyl)picolinate (10). COOMe EtOOC 10 Into a round-bottom flask equipped with a condenser and drying tube were added 9 (0.4210 g, 0.64 mmol), Na2CO3 (0.3400 g, 3.2 mmol), and dry ACN (10 mL). The pale-yellow suspension was heated to reflux over 15 min, after which 6 (0.1508 g, 0.70 mmol, corrected for residual ethyl acetate) was added as a slight suspension in dry ACN (3.5 mL). The mixture was heated at reflux for 44 h and then filtered. The orange filtrate was concentrated at 60 °C under reduced pressure to an orange-brown oil (0.612 g), which was used in the next step without further purification. HRMS (m / z): 590.32021 [M + H]+; Calc: 590.31844. 2026249088  09 Oct 2026

[0147] Preparation of 4-Amino-6-((16-((6-carboxypyridin-2-yl)methyl)-1,4,10,13- tetraoxa-7,16-diazacyclooctadecan-7-yl)methyl)picolinic acid (11-4TFA). Compound 10 (0.612 g) was dissolved in 6 M HCl (7 mL) and heated at 90 °C for 17 h. The orange-brown solution containing slight precipitate was concentrated at 60 °C under reduced pressure to a pale-tan solid. To this solid was added 10% MeOH / H2O containing 0.1% TFA (3 mL). The slight suspension was filtered and the filtrate was purified by preparative HPLC using Method A. Pure fractions were combined, concentrated at 60 °C under reduced pressure, and then lyophilized to give 11 as an off-white solid (0.2974 g, 46% yield over 2 steps). 1H NMR (500 MHz, DMSO-d6) 8= 8.13-8.08 (m, 2H), 7.80 (dd, J = 7.3, 1.6 Hz, 1H), 7.64 (br s), 7.24 (d, J = 2.3 Hz, 1H), 6.76 (d, J = 2.3 Hz, 1H), 4.74 (s, 2H), 4.15 (s, 2H), 3.85 (t, J = 5.0 Hz, 4H), 3.63 (t, J = 5.1 Hz, 4H), 3.57-3.50 (m, 12H), 3.09 (br t, J = 5.2 Hz, 4H). 13C{1H} NMR (126 MHz, DMSO-d6) 8 165.96, 163.37, 159.47, 158.78-157.98 (q, TFA), 151.93, 151.64, 148.25, 144.68, 139.59, 128.43, 124.96, 120.79-113.68 (q, TFA), 109.40, 108.96, 70.03, 69.89, 67.09, 65.16, 57.28, 55.85, 54.47, 53.81. 19F NMR (470 MHz, DMSO-d6) 8= -74.03. EA Found: C, 40.60; H, 4.29; N, 7.04. Calc. for C26H37N5O84CF3COOH: C, 40.69; H, 4.12; N, 6.98. IR (cm-1): 3387, 3161, 1735, 1670, 1204, 1130, 791, 722. HPLC tr = 11.974 min (Method B); 11.546 min (Method D). HRMS (m / z): 548.26883 [M + H]+; Calc: 548.27149.

[0148] Preparation of 6-((16-((6-carboxypyridin-2-yl)methyl)-1,4,10,13-tetraoxa-7,16-diazacyclooctadecan-7- yl)methyl)-4-isothiocyanatopicolinic acid (12, macropa-NCS). A white suspension of 11 (0.1598 g, 0.16 mmol) and Na2CO3 (0.2540 g, 2.4 mmol) was heated at reflux in acetone (10 mL) for 30 min before the slow addition of CSCI2 (305 pL of CSCI2, 2026249088  09 Oct 2026 85%, Acros Organics). The resulting orange suspension was heated at reflux for 3 h and then concentrated at 30 °C under reduced pressure to a pale-orange solid. The solid was dissolved portionwise in 10% ACN / H2O containing 0.2% TFA (8 mL total), filtered, and immediately purified by preparative HPLC using Method C.

[108] Pure fractions were combined, concentrated at RT under reduced pressure to remove the organic solvent, and then lyophilized. Fractions that were not able to be concentrated immediately were frozen at -80 °C. Isothiocyanate 12 was obtained as a mixture of white and pale-yellow solid (0.0547 g) and was stored at -80 °C in a jar of Drierite. Calculations from 1H NMR and 19F NMR spectra of a sample of 12 spiked with a known concentration of fluorobenzene estimated that 12 was isolated as a tetra-TFA salt. 1H NMR (400 MHz, DMSO-d6) 8= 8.17-8.06 (m, 2H), 8.00 (s w / fine splitting, 1H), 7.84 (d, J = 1.5 Hz, 1H), 7.81-7.75 (d w / fine splitting, J = 7.16 Hz, 1H), 4.71 (s, 2H), 4.64 (s, 2H), 3.89-3.79 (m, 8H), 3.62-3.46 (m, 16H). 19F NMR (470 MHz, DMSO-d6) 8= -74.17. IR (cm-1): ~3500-2800, 2083, 2026, 1735, 1670, 1591, 1448, 1183, 1130, 796, 717. HPLC tr = 15.053 min (Method B); 13.885 min (Method D). HRMS (m / z): 590.22600 [M + H]+; Calc: 590.22791.

[0149] Preparation of 6-((16-((6-carboxypyridin-2-yl)methyl)-1,4,10,13-tetraoxa-7,16-diazacyclooctadecan-7-yl)methyl)-4-(3-methylthioureido)picolinic acid (13, macropa-NHC(S)NHCH3). Compound 12 was prepared as described above using 0.0873 g (0.087 mmol) of 11, except the purification step was omitted. Instead, directly to the crude solid was added 2 M methylamine in THF (4 mL). The tan-orange suspension was stirred at RT for 2 h and then concentrated at RT under reduced pressure to a pale-peach solid. The solid was dissolved in 10% ACN / H2O containing 0.2% TFA (2 mL), filtered, and purified by preparative HPLC using Method C. Pure fractions were combined, concentrated at 50 °C under reduced pressure to remove the organic solvent, and then lyophilized. The dark-gold, slightly sticky solid was then recrystallized from ACN with Et2O. The suspension was centrifuged, and the pellet was washed with Et2O (2 x 1.5 mL) and dried in vacuo to give 13 as a tan powder (0.0166 g, 22% unoptimized yield from 11). 1H NMR (600 MHz, DMSO-d6) 8= 10.56 (s, 1H), 8.64 (br s, 1H), 8.26 (s, 1H), 8.16 (s, 1H), 2026249088  09 Oct 2026 8.13-8.02 (m, 2H), 7.81-7.73 (d, J = 7.40 Hz, 1H), 4.74-4.48 (m, 4H), 3.82 (br s, 8H), 3.57 (br s, 8H), 3.54-3.25 (m, 8 H), 2.97 (d, J = 4.4 Hz, 4H). 13C{1H} NMR (126 MHz, DMSO-d6) 8 180.71, 165.44, 165.39, 158.77-157.95 (q, TFA), 151.04, 150.96, 149.79, 147.95, 147.71, 139.22, 127.76, 124.55, 119.68-112.66 (q, TFA), 116.45, 114.85, 69.36, 64.52, 64.50, 57.00, 56.75, 53.42, 53.37, 31.02. 19F NMR (470 MHz, DMSO-d6) 8= -74.49. EA Found: C, 44.66; H, 5.36; N, 9.83. Calc. for C28H40N6O8S-2CF3COOH-1H2O: C, 44.34; H, 5.12; N, 9.70. HPLC tr = 14.067 min (Method B). HRMS (m / z): 621.26799 [M + H]+; Calc: 621.27011.

[0150] Preparation of Macropa-(OCH2CH2)-Ph-NCS A schematic overview of the synthesis of an alternative embodiment of Macropa-NCS, having improved stability is provided in FIG. 3. This compound is evaluated as described below, and useful in the chelation of radionuclides for their conjunction to antibodies, antibody fragments (e.g., antigen-binding fragments), and peptides, and their consequent use in the manufacture of therapeutic compounds and targeted delivery of therapeutic radation. The detailed synthesis information is provided below. OH 1 A solution of compound 1 (0.725g, 3 mmol), Ph3P (0.802g, 3.1 mmol) in CH2Cl2 (15 mL) was cooled to 0 °C under N2. NBS (2.180.545g, 3.3 mmol) was added portion wise for 5 min. The resulting solution was stirred for 2 hrs at 0 °C and concentrated. Resulting crude product was concentrated and purified by combi-flash (5-10% EtOAc in hexane) to give compound 2 (yield= 76%). 2026249088  09 Oct 2026 To a solution of dimethyl 4-hydroxypyridine-2,6-dicarboxylate (0.253g, 1.2mmol) and Cs2CO3 (0.650g, 2 mmol) in DMF (6 mL) was added drop-wise compound 2 (0.299g, 1 mmol) in DMF (2 mL) under a N2 condition. The resulting solution was stirred for 24 hrs at room temperature. The DMF was removed under reduced pressure and water was added, extracted with DCM. Resulting crude product was concentrated and purified by combi-flash (5-10% EtOAc in hexane) to give compound 3 (yield= 21%). Compound 3 (0.215g, 0.5 mmol) was dissolved in DCM: MeOH (2:1, 15 mL) and NaBH4 (0.020g, 0.6mmol) was added in one portion at room temperature (under a N2 condition). The resulting solution was stirred at same temperature for 3 hrs. The solvents were removed and water was added to the resulting residue and extracted into EtOAc. The organic layer was removed under reduced pressure and resulting crude product was purified by combi-flash (50-100% EtOAc in hexane) to give compound 4 (yield= 37%). A solution of compound 4 (0.201g, 0.5mmol), CBr4 (0.198g, 0.6 mmol) and K2CO3 (0.103g, 0.75 mmol) in CH2Cl2 (25 mL) was cooled to 0 °C (under N2) was added drop-wise a solution of PPh3 (0.157g, 0.6 mmol) in (DCM, 5 mL) for 10 min. The resulting reaction mixture was stirred for 12 hrs at room temperature. Solvent was removed to 2026249088  09 Oct 2026 result in a crude reaction mixture, which was purified by combi-flash (EtOAc in hexane) to give compound 5 (yield= 70%). To a clear and colorless solution of 1,7,10,16-tetraoxa- 4,13-diazacyclooctadecane (1.9688 g, 7.5 mmol) and diisopropylethylamine (0.8354 g, 6.5 mmol) in dry ACN (1.075 L) at 75 °C was added dropwise a solution of methyl 6-(chloromethyl)picolinate (0.9255 g, 5.0 mmol) in dry ACN (125 mL) over 2 h 40 min. The flask was then equipped with a condenser and drying tube, and the slightly-yellow solution was heated at reflux for 42 h. Subsequently, the dark-gold solution containing fine, white precipitate was concentrated at 60 °C under reduced pressure to an amber gummy solid, compound 6, which was used in the next step of the synthesis without any further purification. To a stirred solution of compound 6 (0.205g, 0.5 mmol) and diisopropylethylamine (0.129g, 1 mmol) in dry ACN (10 mL) was added compound 5 (0.233g g, 0.5 mmol) in dry ACN (2 mL). The resulting ion solution was stirred at r.t for 12h. Solvent was removed and the crude compound was purified by combi-flash using MeOH in DCM to yield compound 7. 2026249088  09 Oct 2026 Compound 7 (0.08g, 0.1 mmol) was dissolved in aq 6M HCl (5 mL) and stirred at room temperature for 2h-3h. After completion of the starting material (evidenced by LCMS), aq HCl was removed under reduced pressure and the crude reaction mixture, containing compound 8 was used in the next step of the synthesis without any further purification. The crude deboc product was dissolved in THF:1M LiOH (1:1, 5mL) and stirred until completion of the reaction. The resulting crude product was purified by prep-HPLC giving compound 9. NEt3 (7.6 mg, 0.076 mmol) was added to a solution of compound 9 (26 mg, 0.038 mmol) in (8:2) acetonitrile and water (1 mL). Next, di-2-pyridyl thionocarbonate (18m g, 0.076mmol) was added at room temperature and stirred vigorously for 1 h. The crude reaction solution was directly purified by HPLC giving compound 10 (macropa-(OCH2CH2)-Ph-NCS). 2026249088  09 Oct 2026 macropa-(OCH2CH2)-Ph-NCS

[0151] X-Ray Diffraction Studies. Single crystals of H2macropa-2HCl-4H2O suitable for x-ray diffraction were grown from a saturated H2O:acetone (1:5) solution upon standing at room temperature. Single crystals of [La(Hmacropa)(H2O)] -(ClO4)2 were grown via vapor diffusion of THF into an aqueous solution made acidic (pH ~2) upon addition of the complex. Single crystals of [Lu(macropa)]-ClO4’DMF were grown via vapor diffusion of Et2O into a DMF solution of the complex.

[0152] X-ray diffraction data for H2macropa-2HCl-4H2O, [La(Hmacropa)(H2O)]'(ClO4)2, and [Lu(macropa)]-ClO4’DMF were collected on a Bruker APEX 2 CCD Kappa diffractometer (Mo Ka, X = 0.71073 A) at 223 K. The structures were solved through intrinsic phasing using SHELXT

[109] and refined against F2 on all data by full-matrix least squares with SHELXL

[110] following established refinement strategies.

[111] All non-hydrogen atoms were refined anisotropically. Hydrogen atoms were included in the model at geometrically calculated positions and refined using a riding model. Hydrogen atoms bound to nitrogen and oxygen were located in the difference Fourier synthesis and subsequently refined semi-freely with the help of distance restraints. The isotropic displacement parameters of all hydrogen atoms were fixed to 1.2 times the U value of the atoms they are linked to (1.5 times for methyl groups). For [La(Hmacropa)(H2O)]’(ClO4)2, a partially occupied solvent molecule of water was included in the unit cell but could not be satisfactorily modeled. Therefore, that solvent was treated as a diffuse contribution to the overall scattering without using specific atom positions by the solvent masking function in Olex2.

[112] 2026249088  09 Oct 2026

[0153] La3+ and Lu3+ Titrations with Macropa. The pH of a 10 mM 3-(N-morpholino)propanesulfonic acid (MOPS) buffer was adjusted to 7.4 using aqueous NMe4OH. The ionic strength was set at 100 mM using NMe4Cl. Stock solutions of LaCh’6.8H2O (40 mM) and LuCh’6H2O (21 mM) were prepared in 1 mM HCl. A stock solution of H2macropa-2HCl-4H2O (8.8 mM) was prepared in MOPS buffer. From these stock solutions, titration solutions containing macropa (100 pM) and either LaCh or LuCh were prepared in MOPS. Each metal ion titration was carried out at RT by adding 5-10 pL aliquots of titrant to a cuvette containing 3000 pL of macropa (100 pM) in MOPS. Each sample was allowed to equilibrate for 5 min following every addition before a spectrum was acquired. Complexation of the metal ion was monitored by the decrease in absorbance at 268 nm, the kmax of macropa. Titrant was added until no further spectral changes were detected.

[0154] Kinetic Inertness of La3+ and Lu3+ Complexes of Macropa: Transchelation Challenge. A stock solution of ethylenediaminetetraacetic acid (EDTA, 100 mM) was made in MOPS buffer (prepared as described above) by adjusting the pH of the initial suspension to 6.6 using aqueous NMe4OH. A stock solution of diethylenetriaminepentaacetic acid (DTPA, 125 mM) was prepared in H2O by adjusting the pH to 7.4 as described for EDTA. This solution was serially diluted with H2O to yield 12.5 mM and 1.25 mM solutions of DTPA.

[0155] The preformed La3+ and Lu3+ complexes of macropa were challenged with EDTA. Challenges were initiated by adding an aliquot of solution containing EDTA (98.7 mM) and macropa (100 pM) in MOPS buffer to each solution of complex. The final ratios of M:macropa:EDTA were approximately 1:1:20 (La) and 1:1:10 (Lu). Solutions were repeatedly analyzed by UV spectroscopy over the course of 21 days for any spectral changes. The final pH of each solution was between 7.18 and 7.25.

[0156] The complex formed in situ between La3+ and macropa was more rigorously challenged with excess DTPA. A solution containing 500 pM of complex, prepared using the LaCh and macropa stock solutions described above, was left to equilibrate for 5 min. Subsequently, it was portioned into cuvettes and diluted with either 125 mM DTPA, 12.5 mM DTPA, 1.25 mM DTPA, or MOPS to yield solutions containing 1000-, 100-, 10-, or 0-fold excess DTPA and 100 ^M concentration of macropa. These solutions were repeatedly analyzed by UV spectroscopy over the course of 21 days for any spectral changes. The final pH of each solution was between 7.11 and 7.42. 2026249088  09 Oct 2026

[0157] 225Ac Radiolabeling of Macropa and DOTA. 225Ac and 225Ra were produced by the spallation of uranium carbide, separated downstream from other radionuclides by a mass separator using the Isotope Separator and Accelerator (ISAC) isotope separation on-line (ISOL) facility at TRIUMF (Vancouver, BC, Canada), and were collected via literature protocols.[103,104] 225Ac was then separated from 225Ra via DGA column[105,106] (branched, 50-100 pm, Eichrom Technologies LLC) and obtained in 0.05 M HNO3 for use in radiolabeling experiments. Aluminum-backed TLC plates (silica gel 60, F254, EMD Millipore, Darmstadt, Germany) were used to analyze 225Ac radiolabeling reaction progress. Instant thin layer chromatography paper impregnated with silica gel (iTLC-SG, Agilent Technologies, Mississauga, ON, Canada) was used in La3+ and serum stability challenges. TLC plates were developed and then counted on a BioScan System 200 imaging scanner equipped with a BioScan Autochanger 1000 and WinScan software at least 8 h later to allow time for daughter isotopes to decay completely, ensuring that the radioactive signal measured was generated by parent 225Ac. Quantitative radioactivity measurements of 225Ac, 221Fr, and 213Bi were determined via gamma-spectroscopy using a high-purity germanium (HPGe) detector (Canberra GR1520, Meriden, CT) calibrated using a NIST-traceable mixed 133Ba and 152Eu source. Detector dead time was maintained below 10% for all measurements. Data was analyzed using Genie 2000 software (v3.4, Canberra, Meriden, CT).

[0158] Concentration Dependence. Various concentrations of macropa and DOTA were radiolabeled with 225Ac3+ to determine the lowest concentration at which >95% radiolabeling still occurred. Stock solutions of H2macropa-2HCl-4H2O (10-3-10-8 M) and H4DOTA (10-3, 10-5, and 10-7 M) were prepared in H2O. For each radiolabeling reaction, ligand (10 pL) and 225Ac (10-26 kBq, 10-30 pL) were sequentially added to NH4OAc buffer (pH 6, 0.15 M, 150 pL) to give final ligand concentrations of 5.3 x 10-5-5.9 x 10-10 M for macropa and 5.9 x 10-55.9 x 10-9 M for DOTA. The final pH of all labeling reactions was between 5.5 and 6. The reaction solutions were maintained at ambient temperature or 80 °C. Reaction progress was monitored at 5 and 30 min by spotting 3-5 pL of the reaction solution onto TLC plates. The plates were developed with a mobile phase of 0.4 M sodium citrate (pH 4) containing 10% MeOH and then counted. Under these conditions, [225Ac(macropa)]+ and [225Ac(DOTA)]-remained at the baseline (Rf=0) and any unchelated 225Ac (225Ac-citrate) migrated with the solvent front (Rf=1). Radiochemical yields (RCYs) were calculated by integrating area under the peaks on the radiochromatogram and dividing the counts associated with the 225Ac-complex (Rf=0) by the total counts integrated along the length of the TLC plate. 2026249088  09 Oct 2026

[0159] Kinetic Inertness of 225Ac Complexes of Macropa and DOTA.

[0160] General. Stock solutions of La(NO3)3 (0.001 M or 0.1 M) were prepared in H2O. To the radiolabeled samples containing macropa (10 pL of 10-5 M stock; 1.0 x 10-10 moles) or DOTA (10 pL of 10-3 M stock; 1.0 x 10-8 moles) and 225Ac (10 pL, 26 kBq) in NH4OAc buffer (pH 6, 0.15 M, 150 pL), a 50-fold mole excess of La3+was added (5 pL of 0.001 M or 0.1 M stock were added to solutions containing macropa and DOTA, respectively). The solutions were kept at room temperature and analyzed by iTLC at several time points over the course of 8 days. The iTLC plates were developed using citric acid (0.05 M, pH 5) as the eluent. Under these conditions, [225Ac(macropa)]+ and [225Ac(DOTA)]- remained at the baseline (Rf=0) and any unchelated 225Ac (225Ac-citrate) migrated with the solvent front (Rf=1). Percent of complex remaining intact was calculated by integrating area under the peaks on the radiochromatogram and dividing the counts associated with the 225Ac-complex (Rf=0) by the total counts integrated along the length of the iTLC plate.

[0161] Transmetalation by La3+. [225Ac(macropa)]+ and [225Ac(DOTA)]- were prepared using 10-5 M and 10-3 M stock solutions (10 pL) of macropa and DOTA, respectively, to give final ligand concentrations of 5.9 x 10-7 M (macropa) and 5.9 x 10-5 M (DOTA). After confirming a radiochemical yield of >90% by TLC using 0.4 M sodium citrate (pH 4) containing 10% MeOH as the mobile phase, 160 pL of human serum (an equal volume based on labeling reaction volume) were added to each radiolabeled solution. A control solution was also prepared in which water was substituted for ligand. The solutions were monitored over the course of 8 days by iTLC. The plates were developed with EDTA (50 mM, pH 5) as the eluent. Under these conditions, [225Ac(macropa)]+ and [225Ac(DOTA)]- complexes remained at the baseline (Rf=0) and any 225Ac (225Ac-EDTA) that had been transchelated by serum migrated with the solvent front (Rf=1). Percent of complex remaining intact was calculated.

[0162] In Vivo Biodistribution of 225Ac Complexes of Macropa and DOTA. All experiments were approved by the Institutional Animal Care Committee (IACC) of the University of British Columbia and were performed in accordance with the Canadian Council on Animal Care Guidelines. A total of 9 female C57BL / 6 mice (6-8 weeks old, 20-25 g) were used for the biodistribution study of each radiometal complex, n = 3 for each time point.

[0163] Macropa (100 qL of a 1mg / mL solution in NH4OAc) was diluted with 387 qL of NH4OAc (1 M, pH 7), and an aliquot (203 pL) of 225Ac(NO3)3 (~157 kBq) was then added; the pH of this solution was adjusted to 6.5-7 by the addition of 1 M NaOH (210 pL, trace metal 2026249088  09 Oct 2026 grade). After 5 min at ambient temperature, the reaction solution was analyzed by TLC (0.4 M pH 4 sodium citrate as the eluent), which confirmed >95% radiochemical yield. The reaction was allowed to proceed overnight, and the radiochemical yield was again confirmed to be >95% the following morning. At this time, mice were anesthetized by 2% isoflurane, and approximately 100 pL (10-15 kBq) of the [225Ac(macropa)]+ complex were injected into the tail vein of each mouse. After injection, mice were allowed to recover and roam freely in their cages, and were euthanized by CO2 inhalation at 15 min, 1 h, or 5 h (n = 3 at each time point) post-injection. Blood was collected by cardiac puncture and placed into an appropriate test tube for scintillation counting. Tissues collected included heart, liver, kidneys, lungs, small intestine, large intestine, brain, bladder, spleen, stomach, pancreas, bone, thyroid, tail, urine, and feces. Tissues were weighed and then counted with a calibrated gamma counter (Packard, Cobra II model 5002) using three energy windows: 60-120 keV (window A), 180-260 keV (window B), and 400-480 keV (window C). Counting was performed both immediately after sacrifice and after 7 days; counts were decay corrected from the time of injection and then converted to the percentage of injected dose (% ID) per gram of tissue (% ID / g). No differences were noted between the data; therefore, the biodistributions are reported using the data acquired immediately using window A.

[0164] The biodistribution studies of [225Ac(DOTA)]- and 225Ac(NO3)3 were carried out as described above for [225Ac(macropa)]+, with the following modifications. [225Ac(DOTA)- was prepared by adding 225Ac(NO3)3 (338 pL, 1.1 MBq) to a solution of DOTA (100 pg, 20 mg / mL in H2O) in NH4OAC (467 pL, 0.15 M, pH 7). The pH of the solution was adjusted to 7 using NH4OAC (150 pL, 1 M, pH 7) and the solution was heated at 85 °C for 45 min. RCY > 99% was confirmed by TLC as described above. [225Ac(DOTA)]- was diluted with saline to a final concentration of 0.05 MBq / 100 pL, and 100 pL were injected into each mouse. 225Ac(NO3)3 (~58 pL, 0.4 MBq) was diluted and injected in the same manner as [225Ac(DOTA)]-. One mouse that was to be euthanized at the 5 h time point in the [225Ac(DOTA)]- study died shortly after injection. In the same manner, one mouse that was to be euthanized at the 1 h time point in the 225Ac(NO3)3 study died.

[0165] Hydrolysis of Macropa-NCS and p-SCN-Bn-DOTA. To screw-capped vials containing approximately 1 mg of macropa-NCS (compound 12, n = 4) or p-SCN-Bn-DOTA (n = 5) was added 1 mL of 0.1 M pH 9.1 NaHCO3 buffer containing 0.154 M NaCl, which had been passed through a column of pre-equilibrated Chelex. After stirring for 1 min, each solution was filtered through a 0.2 pm PES or PTFE membrane. Five pL aliquots were removed from 2026249088  09 Oct 2026 the vials at various time points over the course of 46-72 h and analyzed by HPLC. Method D was employed for macropa-NCS. Method B was employed for p-SCN-Bn-DOTA using an Epic Polar C18 column, 120 A, 10 pm, 25 cm x 4.6 mm (ES Industries, West Berlin, NJ) at a flow rate of 1 mL / min. Between samplings, the vials were stored at room temperature (23 ± 1 °C) away from light. Hydrolysis was considered complete once the peak at 13.8 min (corresponding to 12) or 18.417 min (corresponding to p-SCN-Bn-DOTA) had disappeared or had negligible integration. A linear regression performed on the plots of ln peak area versus time provided the pseudo-first order rate constant (kobs) as the negative slope. The half-life (t1 / 2) was calculated using the equation t1 / 2 = 0.693 / kobs. The half-life of each compound is reported as the mean ± 1 standard deviation.

[0166] Titration of Macropa-NHC(S)NHCH3 Conjugate with La3+. The titration of the macropa-NHC(S)NHCH3 conjugate (13) with La3+ was carried out at pH 7.4 for macropa, except that the stock solution of 13 (0.760 mM) was prepared in ACN instead of MOPS. The amount of ACN in the sample did not exceed 3.3% by volume. A wait time of 3 min after the addition of each aliquot was found to be sufficient for the sample to reach equilibrium before spectral acquisition. Complexation of the metal ion was monitored using the increase in absorbance at 300 nm. The pH of the solution at the end of the titration was 7.43.

[0167] Kinetic Inertness of La-Macropa-NHC(S)NHCH3: Transchelation Challenge. Solutions of diethylenetriaminepentaacetic acid (DTPA; 125 mM and 12.5 mM) were prepared in MOPS buffer (pH 7.4). A MOPS solution containing macropa-NHC(S)NHCH3 (126.7 pM, 16.7% ACN by volume) and LaCh (126.2 pM) was prepared using the stock solutions described above and was left to equilibrate for 10 min. Subsequently, it was portioned into cuvettes and diluted with either 125 mM DTPA, 12.5 mM DTPA, or MOPS to yield solutions containing 1000-, 100-, or 0-fold excess DTPA. The final concentration of macropa-NHC(S)NHCH3 in each cuvette was 25.3 pM. These solutions were repeatedly analyzed by UV spectrophotometry over the course of 21 days for any spectral changes. The final pH of each solution was between 7.42 and 7.49. The experiment was performed in triplicate.

[0168] Exemplary Synthesis and Biological Activity of 225Ac-macropa-RPS-070

[0169] Preparation of Di-tert-butyl (((S)-1-(tert-butoxy)-6-(3-(3-ethynylphenyl)ureido)-1-oxohexan-2-yl)carbamoyl)-L-glutamate (214). Alkyne 214 was prepared according to published methods

[247] and isolated as an off-white powder. 1H NMR (500 MHz, CDCl3) 8= 7.90 (s, 1H), 7.58 (t, 1H, J = 1.7 Hz), 7.51 (dd, 1H, J1 = 8.2 Hz, J2 = 1.3 Hz), 7.18 (t, 1H, J = 7.9 Hz), 7.05 (d, 1H, J = 7.7 Hz), 6.38 (d, 1H, J = 7.9 Hz), 6.28 (br s, 1H), 5.77 (d, 1H, J = 6.9 Hz), 4.32 (m, 1H), 4.02 (m, 1H), 3.53 (m, 1H), 3.05 (m, 1H), 3.00 (s, 1H), 2.39 (m, 2H), 2.07 (m, 1H), 1.88 (m, 1H), 1.74 (m, 1H), 1.62 (m, 1H), 1.491.37 (m, 4H), 1.41 (s, 18H), 1.37 (s, 9H).

[0170] Preparation of 2,5-Dioxopyrrolidin-1-yl N2-(((9H-fluoren-9-yl)methoxy)carbonyl)-N6-(tert- butoxycarbonyl)-L-lysinate (215). A suspension of Fmoc-L-Lys(Boc)-OH (5.0 g, 10.7 mmol) and N, N‘-disuccinimidyl carbonate (2.74 g, 10.7 mmol) in CH2Cl2 (50 mL) was stirred at room temperature under argon. Then DIPEA (1.86 mL, 10.7 mmol) was added, and the suspension was stirred overnight. The solvent was evaporated under reduced pressure and the crude product was purified by flash chromatography (0-100% EtOAc in hexane). Lysine 215 was isolated as a white powder (2.5 g, 41%). 1H NMR (500 MHz, CDCI3) 8= 7.76 (d, 2H, J = 7.6 Hz), 7.59 (d, 2H, J = 7.3 Hz), 7.40 (t, 2H, J = 7.4 Hz), 7.32 (t, 2H, J = 7.3 Hz), 5.46 (br s, 1H), 4.71 (m, 2H), 4.45 (m, 2H), 4.23 (t, 1H, J = 6.6 Hz), 3.14 (br s, 2H), 2.85 (s, 4H), 2.02 (m, 1H), 1.92 (m, 1H), 1.58 (m, 4H), 1.44 (s, 9H). 2026249088  09 Oct 2026

[0171] Preparation of tert-Butyl N2-(N2-(((9H-fluoren-9-yl)methoxy)carbonyl)-N6-(tert-butoxycarbonyl)-L- lysyl)-N6-((benzyloxy)carbonyl)-L-lysinate (216). NHBoc O CO2tBu 216 A suspension of L-Lys(Z)-OtBu-HCl (1.49 g, 4.0 mmol) in CH2CI2 (15 mL) was treated with DIPEA (0.87 mL, 5.0 mmol). To the resulting mixture was added a solution of lysine 215 (2.2 g, 3.9 mmol) in CH2Cl2 (10 mL), and the reaction was stirred overnight at room temperature under argon. It was then washed with saturated NaCl solution, and the organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (0-100% EtOAc in hexane), and di-lysine 216 was isolated as a white powder (2.2 g, 72%). 1H NMR (500 MHz, CDCb) 8= 7.76 (d, 2H, J = 7.5 Hz), 7.59 (d, 2H, J = 7.3 Hz), 7.40 (t, 2H, J = 7.5 Hz), 7.32 (m, 8H), 6.69 (br s, 1H), 5.60 (br s, 1H), 5.06 (m, 4H), 4.72 (br s, 1H), 4.43 (m, 1H), 4.38 (m, 1H), 4.21 (m, 1H), 3.14 (m, 4H), 1.85 (m, 2H), 1.73 (m, 2H), 1.50 (m, 4H), 1.46 (s, 9H), 1.44 (s, 9H), 1.39 (m, 4H).

[0172] Preparation of 2,5-Dioxopyrrolidin-1-yl 2-(4-iodophenyl)acetate (217). A solution of 2-(4-iodophenyl)acetic acid (786 mg, 3.0 mmol) and EDC-HCl (671 mg, 3.5 mmol) in CH2Cl2 (20 mL) was stirred for 15 min at room temperature under argon. Then N-hydroxysuccinimide (368 mg, 3.2 mmol) and NEt3 (0.56 mL, 4.0 mmol) were added and the reaction was stirred for 7 h. It was then washed with saturated NaCl solution, and the organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by flash chromatography (0-100% EtOAc in hexane), and the NHS ester 217 was isolated as a white solid (760 mg, 70%). 1H NMR (500 MHz, CDCl3) 8= 7.69 (d, 2H, J = 7.9 Hz), 7.09 (d, 2H, J = 7.9 Hz), 3.88 (s, 2H), 2.83 (s, 4H). 2026249088  09 Oct 2026

[0173] Preparation of tert-Butyl N2-(N2-(1-azido-3,6,9,12,15,18-hexaoxahenicosan-21-oyl)-N6-(tert-butoxycarbonyl)-L-lysyl)-N6-((benzyloxy)carbonyl)-L-lysinate (218). To a solution of Fmoc-protected di-lysine 216 (768 mg, 0.97 mmol) in CH2Cl2 (4 mL) was added NHEt2 (2.07 mL, 20 mmol). The solution was stirred overnight at room temperature. The solvents were removed under reduced pressure, and the crude product, a yellow oil, was used without further purification. To a solution of this oil (183 mg, 0.32 mmol) in CH2Cl2 (3 mL) were added successively solutions of NEt3 (57 pL, 0.41 mmol) in CH2CI2 (1 mL) and azido-PEG6-NHS ester (100 mg, 0.21 mmol; Broadpharm, USA) in CH2Cl2 (1 mL), and the reaction was stirred overnight at room temperature. It was then diluted with CH2Cl2 and washed successively with H2O and saturated NaCl solution. The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure to give azide 218 as a colorless oil (184 mg; 95%) without need for further purification. Mass (ESI+): 926.4 [M+H]+. Calc. Mass = 925.54.

[0174] Preparation of Di-tert-butyl (((S)-1-(tert-butoxy)-6-(3-(3-(1-((9S,12S)-9-(tert-butoxycarbonyl)-12-(4-((tert-butoxycarbonyl)amino)butyl)-3,11,14-trioxo-1-phenyl-2,17,20,23,26,29,32-heptaoxa-4,10,13-triazatetratriacontan-34-yl)-1H-1,2,3-triazol-4-yl)phenyl)ureido)-1-oxohexan-2-yl)carbamoyl)-L-glutamate (219). A solution of 100 pL of 0.5 M CuSO4 and 100 pL of 1.5 M sodium ascorbate in DMF (0.5 mL) was mixed for 5 min and was then added to a solution of 218 (184 mg, 0.20 mmol) and 214 (132 mg, 0.21 mmol) in DMF (2.5 mL). The resulting mixture was stirred at room temperature for 45 min. It was then concentrated under reduced pressure and the crude residue was purified by flash chromatography (0-30% MeOH in EtOAc) to give triazole 219 as an orange oil (285 mg; 87%). Mass (ESI+): 1557.2 [M+H]+. Calc. Mass = 1555.90. 2026249088  09 Oct 2026

[0175] Preparation of Di-tert-butyl (((S)-1-(tert-butoxy)-6-(3-(3-(1-((23S,26S)-26-(tert-butoxycarbonyl)-23-(4-((tert-butoxycarbonyl)amino)butyl)-33-(4-iodophenyl)-21,24,32-trioxo-3,6,9,12,15,18-hexaoxa-22,25,31-triazatritriacontyl)-1H-1,2,3-triazol-4- yl)phenyl)ureido)-1-oxohexan-2-yl)carbamoyl)-L-glutamate (220). Cbz-Protected triazole 219 (285 mg, 0.18 mmol) was dissolved in MeOH (15 mL) in a two-neck flask. To the solution was added 10% Pd / C (20 mg), and the suspension was shaken and the flask evacuated. The suspension was then placed under an H2 atmosphere and stirred overnight. It was filtered through celite, and the filter cake was washed three times with MeOH. The combined filtrate was concentrated under reduced pressure to give the free amine as a colorless oil (117 mg; 45%) that was used without further purification. Mass (ESI+): 1423.8 [M+H]+. Calc. Mass = 1422.77. To a solution of the amine (117 mg, 82 p.mol) in CH2CI2 (4 mL) was added a solution of DIPEA (23 ^L, 131 mmol) in CH2CI2 (1 mL), and the mixture was stirred at room temperature under argon. Then a solution of 217 (37 mg, 103 p.mol) in CH2Cl2 (2 mL) was added, and the reaction was stirred at room temperature for 2 h. It was then poured into H2O (10 mL) and the layers were separated. The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure to give the crude product as a colorless semi-solid. The crude product was purified by prep TLC (10% MeOH in EtOAc) to give phenyl iodide 220 as a colorless oil (34 mg; 25%). Mass (ESI+): 1666.6 [M+H]+. Calc. Mass = 1665.80.

[0176] Preparation of (((S)-1-Carboxy-5-(3-(3-(1-((23S,26S)-26-carboxy-23-(4-(3-(2-carboxy-6-((16-((6-carboxypyridin-2-yl)methyl)-1,4,10,13-tetraoxa-7,16- diazacyclooctadecan-7-yl)methyl)pyridin-4-yl)thioureido)butyl)-33-(4-iodophenyl)- 2026249088  09 Oct 2026 21,24,32-trioxo-3,6,9,12,15,18-hexaoxa-22,25,31-triazatritriacontyl)-1H-1,2,3-triazol-4-yl)phenyl)ureido)pentyl)carbamoyl)-L-glutamic acid (221, macropa-RPS-070). To a solution of 220 (34 mg, 20 p.mol) in CH2CI2 (2 mL) was added TFA (0.5 mL), and the reaction was stirred at room temperature for 5 h. It was then concentrated under reduced pressure, and the crude product was diluted with H2O and lyophilized to give the free amine as a TFA salt. Mass (ESI+): 1342.5 [M+H]+. Mass (ESI-): 1340.6 [M-H]-. Calc. Mass = 1341.50. To a solution of the amine (9 mg, 6.7 p.mol) in DMF (0.5 mL) was added a solution of macropa-NCS (15 mg, 25.4 p.mol) in DMF (0.5 mL). Then DIPEA (300 ^L, 1.72 mmol) was added and the reaction was stirred at room temperature for 2 h. The volatiles were removed under reduced pressure and the crude product was purified by prep HPLC to give macropa-RPS-070 (221) as a white powder (5.4 mg; 42%). Mass (ESI+): 1932.76 [M+H]+. 1931.09 [M+H]-. Calc. Mass = 1931.91.

[0177] Preparation of Radiosynthesis of 225Ac-macropa-RPS-070.

[0178] General. All reagents were purchased from Sigma Aldrich unless otherwise noted, and were reagent grade. Hydrochloric acid (HCl) was traceSELECT® (>99.999%) for trace analysis quality. Aluminum-backed silica thin layer chromatography (TLC) plates were purchased from Sigma Aldrich. Stock solutions of 0.05 M HCl and 1 M NH4OAc were prepared by dilution in Milli-Q® water.

[0179] Radiolabeling Procedure. To a solution of 225Ac(NO3)3 (Oak Ridge National Laboratory, USA) in 0.05 M HCl (17.9 MBq in 970 ^L) was added 20 ^L of a 1 mg / mL 2026249088  09 Oct 2026 solution of macropa-RPS-070 in DMSO. The pH was raised to 5-5.5 by addition of 90 pL 1 M NH4OAc. The reaction was allowed to stand at room temperature for 20 min with periodic shaking. Then, 200 pL of the reaction solution was removed and diluted with 3.8 mL of normal saline (0.9% NaCl in deionized H2O; VWR) to give a solution with a concentration of 910 kBq / mL. An aliquot was removed from the final solution and spotted onto an aluminum-backed silica TLC plate to determine radiochemical yield. An aliquot of the 225Ac(NO3)3 solution in 0.05M HCl was spotted in a parallel lane as a control. The plate was immediately run in a 10% v / v MeOH / 10mM EDTA mobile phase, and then allowed to stand for 8 h to enable radiochemical equilibrium to be reached. The plate was visualized on a Cyclone Plus Storage Phosphor System (Perkin Elmer) following a 3-min exposure on the phosphor screen. The radiochemical yield was expressed as a ratio of 225Ac-macropa-RPS-070 to total activity and was determined to be 98.1%.

[0180] Biodistribution Studies with 225Ac-macropa-RPS-070.

[0181] Cell Culture. The PSMA-expressing human prostate cancer cell line, LNCaP, was obtained from the American Type Culture Collection. Cell culture supplies were from Invitrogen unless otherwise noted. LNCaP cells were maintained in RPMI-1640 medium supplemented with 10% fetal bovine serum (Hyclone), 4 mM L-glutamine, 1 mM sodium pyruvate, 10 mM N-2-hydroxyethylpiperazine-N-2-ethanesulfonic acid (HEPES), 2.5 mg / mL D-glucose, and 50 pg / mL gentamicin in a humidified incubator at 37 °C / 5% CO2. Cells were removed from flasks for passage or for transfer to 12-well assay plates by incubating them with 0.25% trypsin / ethylenediaminetetraacetic acid (EDTA).

[0182] Inoculation of Mice with Xenografts. All animal studies were approved by the Institutional Animal Care and Use Committee of Weill Cornell Medicine and were undertaken in accordance with the guidelines set forth by the USPHS Policy on Humane Care and Use of Laboratory Animals. Animals were housed under standard conditions in approved facilities with 12 h light / dark cycles. Food and water was provided ad libitum throughout the course of the studies. Hairless male nu / nu mice were purchased from the Jackson Laboratory. For inoculation in mice, LNCaP cells were suspended at 4 x 107 cells / mL in a 1:1 mixture of PBS:Matrigel (BD Biosciences). Each mouse was injected in the left flank with 0.25 mL of the cell suspension. Biodistributions were conducted when tumors were in the range 100-400 mm3.

[0183] Biodistribution of 225Ac-macropa-RPS-070 in LNCaP xenograft mice. Fifteen LNCaP xenograft tumor-bearing mice (5 per time point) were injected intravenously with a bolus injection of 85-95 kBq and 100 ng (50 pmol) of each ligand. The mice were sacrificed by 2026249088  09 Oct 2026 cervical dislocation at 4, 24 and 96 h post injection. A blood sample was removed, and a full biodistribution study was conducted on the following organs (with contents): heart, lungs, liver, small intestine, large intestine, stomach, spleen, pancreas, kidneys, muscle, bone, and tumor. Tissues were weighed and counted on a 2470 Wizard Automatic Gamma Counter (Perkin Elmer). 1% ID / mL samples were counted prior to and following each set of tissue samples to enable decay correction to be undertaken. Counts were corrected for decay and for activity injected, and tissue uptake was expressed as percent injected dose per gram (% ID / g). Standard error measurement was calculated for each data point. 2026249088  09 Oct 2026 Table F. Organ distribution of 225Ac-macropa-RPS-070 at t = 4 h, 24 h, and 96 h following intravenous injection in LNCaP xenograft mice (n = 5 per time point). Values expressed as % ID / g. 2026249088  09 Oct 2026 4h 1 2 3 4 5 Mean SEM Blood 0.90654 0.55246 1.11808 0.8276 0.65638 0.81221 0.0986 Heart 0.75759 0.65317 0.77395 0.75148 0.6585 0.71894 0.02604 Lungs 0.99558 0.60669 1.25979 0.98587 0.88664 0.94691 0.10516 Liver 1.62187 1.34632 1.74207 1.68077 1.3957 1.55735 0.0788 Small Intestine 0.1998 0.16282 0.3104 0.24413 0.17094 0.21762 0.02721 Large Intestine 1.36298 0.65162 1.27419 0.91656 0.81901 1.00487 0.13563 Stomach 0.33963 0.2471 0.30417 0.4109 0.21221 0.3028 0.03489 Spleen 1.40902 0.70804 1.61264 1.10815 0.8756 1.14269 0.16632 Pancreas 0.55487 0.41637 0.55317 0.4675 0.6604 0.53047 0.04182 Kidneys 65.5884 20.5274 108.233 33.654 33.0707 52.2146 15.8618 Muscle 0.68006 0.80579 0.72817 0.67666 0.65617 0.70937 0.02684 Bone 1.14861 1.12335 1.48731 0.92036 1.15463 1.16685 0.09106 Tumor 6.73177 10.7309 23.8367 15.3682 7.50352 12.8342 3.1429 24h 1 2 3 4 5 Mean SEM Blood 0.34825 0.31324 0.22083 0.29453 0.27697 0.29076 0.0211 Heart 0.52256 0.56334 0.4521 0.47914 0.46483 0.49639 0.02052 Lungs 0.53778 0.45077 0.46083 0.4286 0.44831 0.46526 0.01887 Liver 1.57844 1.47552 1.13776 1.14264 1.48473 1.36382 0.09305 Small Intestine 0.08784 0.09914 0.08822 0.09466 0.10376 0.09473 0.00309 Large Intestine 0.13296 0.1259 0.13252 0.13425 0.13176 0.13148 0.00145 Stomach 0.1296 0.12119 0.1119 0.14675 0.15329 0.13255 0.00773 Spleen 0.62075 0.65764 0.62013 0.57685 0.58554 0.61218 0.01443 Pancreas 0.39847 0.39119 0.50347 0.33315 0.31944 0.38914 0.03252 Kidneys 4.98792 4.25707 3.94586 3.66457 4.10348 4.19178 0.22185 Muscle 0.61193 0.5149 0.44832 0.78028 0.44579 0.56025 0.06276 Bone 1.27255 1.06645 0.83943 1.00576 0.69755 0.97635 0.09828 Tumor 11.6163 9.26927 7.50158 4.41446 8.04683 8.16969 1.17583 96h 1 2 3 4 5 Mean SEM Blood 0.19042 0.19188 0.15206 0.16528 0.23822 0.18757 0.01475 Heart 0.39939 0.42398 0.42861 0.45863 0.45595 0.43331 0.01098 Lungs 0.30165 0.50912 0.46944 0.37811 0.36979 0.40562 0.03717 Liver 0.79406 0.8144 0.73301 0.7917 0.79415 0.78546 0.01374 Small Intestine 0.04372 0.0577 0.03752 0.04431 0.04136 0.04492 0.00341 Large Intestine 0.04349 0.09663 0.04522 0.04198 0.03927 0.05332 0.01087 Stomach 0.03442 0.04708 0.03448 0.02845 0.02366 0.03362 0.00393 Spleen 0.48373 0.394 0.44261 0.43481 0.53966 0.45896 0.02469 Pancreas 0.09848 0.37696 0.30549 0.31625 0.33352 0.28614 0.04847 Kidneys 1.30286 1.3239 2.00405 1.39866 1.45955 1.4978 0.12958 Muscle 0.3022 0.52492 0.25089 0.29815 0.2528 0.32579 0.05095 Bone 0.86391 0.86874 0.83831 1.12223 0.82042 0.90272 0.05557 Tumor 4.04259 4.07799 6.73954 4.58107 4.84503 4.85724 0.49449 2026249088  09 Oct 2026

[0184] Conjugation of Macropa-NCS and p-SCN-Bn DOTA to Trastuzumab.

[0185] General. All glassware was washed overnight in 1M HCl. Saline (0.154 M NaCl) and all buffer solutions were passed through a column of Chelex-100 pre-equilibrated with the appropriate buffer. Trastuzumab (Tmab, Genentech) was purified using a Zeba spin desalting column (2 mL or 5 mL, 40 MWCO, Thermo Scientific, Waltham, MA) according to the manufacturer’s protocol, with saline as the mobile phase. The concentration of purified Tmab was calculated via the Beer-Lambert law using A280 and an S280 of 1.446 mL mg-1 cm-1.

[107] Purified Tmab and Tmab conjugates were stored at 4 °C.

[0186] Conjugation of Macropa-NCS to Tmab. A stock solution containing 4.4 mg / mL of macropa-NCS (12) was prepared in 0.1 M pH 9.1 NaHCO3 buffer containing 0.154 M NaCl and was stored at -80 °C. The stability of 12 during storage was verified by analytical HPLC. To a portion of Tmab in saline (74 pL) were added 12 (52 ^L) and NaHCO3 buffer (266 ^L), so that the final concentrations of Tmab and 12 were 5.1 mg / mL and 0.59 mg / mL, respectively. Macropa-NCS was estimated to be in 16-fold molar excess to Tmab based on a molecular weight of 1045.76 g / mol for 12 (tetra-TFA salt). The pH of this solution was between 8 and 9 by litmus paper. The solution was rocked gently at room temperature for 17.5 h and then purified using a spin column.

[0187] Conjugation of p-NCS-Bn-DOTA to Tmab. A stock solution containing 3.05 mg / mL of p-NCS-Bn-DOTA was prepared in H2O and stored at -80 °C. To a portion of Tmab in saline (66 ^L) were added p -NCS-Bn-DOTA (49 ^L) and NaHCO3 buffer (274.5 pL), so that the final concentrations of Tmab and p-NCS-Bn-DOTA were 5.1 mg / mL and 0.38 mg / mL (16-fold molar excess of L), respectively. The pH of this solution was between 8 and 9 by litmus paper. The solution was rocked gently at room temperature for 17.5 h and then purified using a spin column.

[0188] Determination of Conjugate Protein Concentration by BCA Assay. The concentration of protein in macropa-Tmab and DOTA-Tmab conjugates was determined using the PierceTM BCA Protein Assay kit (Thermo Scientific, Waltham, MA, microplate protocol). Tmab was employed as the protein standard. A stock solution of purified Tmab was diluted with saline and the concentration of this solution (1.83 mg / mL) was determined using a NanoDrop 1000 Spectrophotometer (Thermo Scientific, Waltham, MA). The standard curve was linear (r2 = 0.9966) over the concentration range measured (0-1828 ^g / mL). The protein concentration of each conjugate was calculated from two independent dilutions, each measured 2026249088  09 Oct 2026 in triplicate, and the results were averaged to give a protein concentration of 4.557 mg / mL for macropa-Tmab and 2.839 mg / mL for DOTA-Tmab.

[0189] Ligand-to-Protein Ratio Analysis by MALDI-ToF. The average number of macropa or DOTA ligands conjugated to Tmab was determined by MALDI-ToF MS / MS on a Bruker autoflex speed at the Alberta Proteomics and Mass Spectrometry Facility (University of Alberta, Canada) using a procedure described elsewhere.

[108] Purified Tmab and the conjugates were analyzed in duplicate, and the [M+H]+ mass signals from the chromatograms were averaged for each compound. The ligand-to-protein (L:P) ratio for each conjugate was obtained by subtracting the molecular weight of Tmab from the molecular weight of the conjugate, and subsequently dividing by the mass of the bifunctional ligand.

[0190] 225Ac Radiolabeling of Tmab Conjugates and Serum Stability of Complexes.

[0191] General. Instant thin layer chromatography paper impregnated with silica gel (iTLC-SG, Agilent Technologies, Mississauga, ON, Canada) was used to monitor the progress of 225Ac radiolabeling reactions and to determine serum stability. TLC plates were developed as described below and then counted on a BioScan System 200 imaging scanner equipped with a BioScan Autochanger 1000 and WinScan software at least 8 h later to allow time for daughter isotopes to decay completely, ensuring that the radioactive signal measured was generated by parent 225Ac.

[0192] 225Ac Radiolabeling Studies. In a total reaction volume of 200 pL made up with NH4OAC buffer (pH 6, 0.15 M), 225Ac (10 or 20 kBq, 7-10 pL) was mixed with 25-100 pg of either macropa-Tmab (5.5-22 pL) or DOTA-Tmab (8.81-35.2 pL), and the pH was adjusted to ~5 with NaOH. A control solution was also prepared in which unmodified Tmab (25 pg) was substituted in place of conjugate. The reaction solutions were maintained at ambient temperature and analyzed at 5 min, 30 min, 1 h, 2 h, 3 h, and 4 h by spotting 8 pL in triplicate on iTLC strips. The strips were developed with a mobile phase of 0.05 M citric acid (pH 5). Under these conditions, 225Ac-macropa-Tmab and 225Ac-DOTA-Tmab remained at the baseline of the plate (Rf=0) and any unchelated 225Ac (225Ac -citrate) migrated with the solvent front (Rf=1). Radiochemical yields (RCYs) were calculated by integrating area under the peaks on the radiochromatogram and dividing the counts associated with the 225Ac-complex (Rf=0) by the total counts integrated along the length of the TLC plate.

[0193] Stability of 225Ac-macropa-Tmab in Human Serum. A solution of 225Ac-macropa-Tmab was prepared using 100 pg of protein. After confirmation by TLC that a RCY of >95% 2026249088  09 Oct 2026 had been achieved, human serum was thawed to room temperature and added to the radiolabeled immunoconjugate to give a solution containing 90% serum by volume. The sample was incubated at 37 °C. At various time points over the course of 7 days, aliquots (15-30 pL) were removed from the sample and spotted in triplicate onto iTLC strips. The strips were developed using an EDTA (50 mM, pH 5.2) mobile phase and counted. Under these conditions, 225Ac-macropa-Tmab remained at the baseline (Rf=0) and any 225Ac (225Ac-EDTA) that had been transchelated by serum migrated with the solvent front (Rf=1). Percent of complex remaining intact was calculated.

[0194] As an additional challenge, separate aliquots (39 ^L) were also removed from the serum sample on days 1 and 7 and mixed with 50 mM DTPA (pH 7, 13 pL) to challenge off any 225Ac that was only loosely bound by the radioimmunoconjugate. After incubation of this solution at 37 °C for 15 minutes, an aliquot (30 pL) was spotted in triplicate on iTLC plates and developed using an EDTA (50 mM, pH 5.2) mobile phase. Percent of complex remaining intact was calculated.

[0195] In Vivo Biodistribution Studies of [225Ac(macropa)]+, [225Ac(DOTA)]-, and 225Ac(NO3)31

[0196] Table 1. Organ distribution of 225Ac complexes following intravenous injection in mice. Adult C57BL / 6 mice were injected with [225Ac(macropa)]+, [225Ac(DOTA)]-, or 225Ac(NO3)3 and sacrificed after 15 min, 1 h, or 5 h. Values for each time point are given as % ID / g (n=3) using energy window A (60-120 keV). Organ 15 min SD 1 h SD 5 h SD [225Ac(macropa)]+ blood 5.11 2.82 0.40 0.38 0.01 0.01 urine 1378.82 971.53 489.11 26.75 12.78 6.10 feces 0.91 1.18 0.28 0.14 3.46 1.06 heart 2.19 0.60 0.31 0.24 0.10 0.11 liver 2.28 0.41 0.75 0.18 0.39 0.03 kidneys 27.55 7.51 13.36 17.13 0.74 0.06 lungs 5.98 1.81 0.51 0.36 0.01 0.04 small intestines 2.64 1.08 1.10 0.47 0.29 0.20 2026249088  09 Oct 2026 large intestines 2.40 0.52 0.36 0.10 0.49 0.22 brain 0.26 0.09 0.12 0.07 0.02 0.02 bladder 46.74 24.65 6.23 7.44 4.25 5.27 spleen 2.52 1.08 0.51 0.19 0.11 0.03 stomach 2.97 0.72 0.41 0.08 0.01 0.06 pancreas 1.46 0.64 0.19 0.16 0.10 0.06 bone (femur + joint) 2.52 0.34 0.31 0.16 0.05 0.10 thyroids 28.23 17.90 3.18 2.21 0.10 7.95 tail 8.84 1.56 1.82 1.11 0.14 0.09 [225Ac(DOTA)] — blood 5.2881 2.9807 0.1144 0.0203 0.0140 0.0024 urine 1467.9186 1073.9229 158.6102 141.1945 1.1612 0.3653 feces 6.2730 8.7284 0.2035 0.2433 5.5318 1.7685 heart 2.3335 0.7337 0.1012 0.0853 0.0664 0.0091 liver 2.2520 0.5051 0.2715 0.1973 0.1010 0.0063 kidneys 27.6566 6.8974 1.4020 0.2124 0.6172 0.0168 lungs 5.7556 1.7234 0.1555 0.0800 0.0390 0.0135 small intestines 2.6370 1.3350 1.7207 2.1165 0.0967 0.0232 large intestines 2.3348 0.7436 0.1229 0.0551 0.2026 0.1073 brain 0.2655 0.0598 0.0224 0.0123 0.0213 0.0021 bladder 48.2703 26.4988 4.7351 4.9621 0.3551 0.0335 spleen 2.5905 1.3909 0.0938 0.0322 0.1380 0.0733 stomach 2.7440 0.8312 0.1367 0.1078 0.0852 0.0100 pancreas 1.5090 0.6828 0.0743 0.0752 0.0677 0.0090 bone (femur + joint) 2.6298 0.6802 0.4487 0.0586 0.2063 0.0231 thyroids -5.7725 27.0550 2.3564 2.7015 3.6425 1.8897 tail 8.8606 1.1879 0.8091 0.1272 0.3057 0.0766 2026249088  09 Oct 2026 225Ac(NO3)3 blood 40.966 6.455 20.8234 0.8102 1.9886 0.5457 urine 5.527 3.460 4.5194 0.4803 4.8267 3.6549 feces 0.240 0.070 0.2189 0.1167 0.9445 0.7998 heart 8.557 2.698 4.4261 1.2771 1.3450 0.2326 liver 22.899 1.788 39.8269 4.5062 59.8156 10.4928 kidneys 10.468 1.897 7.2170 1.5026 4.6910 2.3005 lungs 12.757 2.883 8.2412 1.9189 4.1871 3.8011 small intestines 2.002 0.094 1.5594 0.3191 1.3704 0.4345 large intestines 1.116 0.145 0.6035 0.4502 0.6479 0.2782 brain 0.614 0.283 0.2995 0.0893 0.0452 0.0343 bladder 1.477 0.689 0.9047 0.0759 1.4947 2.4402 spleen 22.733 4.962 34.8831 1.6768 62.9614 12.7041 stomach 2.348 0.250 1.6211 0.0147 2.6131 1.4450 pancreas 2.366 0.922 2.1771 0.8907 0.4874 0.4300 bone (femur + joint) 2.764 0.757 2.4707 0.1198 3.5460 0.6374 thyroids 4.391 1.511 2.5988 4.9499 -2.7052 2.9758 tail 7.459 5.674 5.7939 1.8506 23.4055 19.5704

[0197] Table 2. Organ distribution of 225Ac complexes following intravenous injection in mice. Adult C57BL / 6 mice were injected with [225Ac(macropa)]+, [225Ac(DOTA)]-, or 225Ac(NO3)3 and sacrificed after 15 min, 1 h, or 5 h. Values for each time point are given as % ID / g (n=3) using energy window B (180-260 keV). Organ 15 min SD 1 h SD 5 h SD [225Ac(macropa)]+ blood 5.23 2.93 0.39 0.38 0.00 0.01 urine 1541.60 1105.98 517.19 11.65 13.51 6.04 feces 1.04 0.92 0.27 0.21 3.49 1.18 heart 2.39 0.80 0.20 0.31 -0.04 0.12 2026249088  09 Oct 2026 liver 2.17 0.40 0.70 0.16 0.36 0.01 kidneys 27.86 7.39 12.97 17.16 0.78 0.14 lungs 5.83 1.81 0.54 0.25 -0.05 0.14 small intestines 2.59 1.19 0.94 0.46 0.29 0.21 large intestines 2.53 0.57 0.22 0.18 0.45 0.27 brain 0.23 0.06 0.12 0.11 -0.01 0.04 bladder 47.64 25.00 5.92 8.15 3.69 6.69 spleen 2.55 1.54 0.23 0.26 0.09 0.06 stomach 3.29 1.03 0.33 0.26 0.04 0.14 pancreas 1.63 0.73 0.12 0.22 -0.12 0.16 bone (femur + joint) 2.69 0.63 0.17 0.11 0.02 0.01 thyroids -2.22 12.06 0.10 5.33 -6.94 8.77 tail 9.39 1.59 1.82 1.04 0.13 0.05 [225Ac(DOTA)] — blood 5.6357 3.2852 0.1127 0.0403 0.0292 0.0172 urine 1635.4394 1233.7980 159.1628 143.0187 3.6967 3.3377 feces 1.0222 0.9859 0.2349 0.2923 3.3534 1.0198 heart 2.7276 0.7955 0.1378 0.1197 0.0879 0.0591 liver 2.1817 0.4921 0.2672 0.1890 0.2712 0.2370 kidneys 28.0858 6.9019 1.2560 0.1319 0.6718 0.1380 lungs 6.0147 1.8416 0.1946 0.1077 0.1289 0.0320 small intestines 2.5009 1.2567 1.8809 2.3424 0.2065 0.1617 large intestines 2.5365 0.7142 0.0813 0.0554 0.2527 0.1980 brain 0.2735 0.1473 0.0248 0.0120 0.0513 0.0110 bladder 54.4696 32.7034 4.7141 5.1077 0.7521 0.0884 spleen 2.9076 1.5773 0.0825 0.0965 0.0834 0.2219 stomach 2.7311 0.9322 0.1379 0.1390 0.1789 0.0565 pancreas 1.4929 1.2189 0.0746 0.0806 0.1266 0.0354 2026249088  09 Oct 2026 bone (femur + joint) 3.0357 0.7199 0.4126 0.0368 0.1478 0.1689 thyroids 1.6601 7.1867 2.6514 6.1376 16.2357 11.0860 tail 9.4746 1.5429 0.8973 0.0672 0.1634 0.0768 225AC(NO3)3 blood 41.5628 6.0720 21.4460 1.0862 2.0018 0.5989 urine 5.0951 2.4036 7.0564 2.0984 3.3142 2.6426 feces 0.3857 0.1799 0.3300 0.1741 1.0201 0.9002 heart 8.3605 2.5149 4.5832 1.4669 1.3948 0.3318 liver 23.6091 2.1849 41.0995 5.1387 62.0765 10.0091 kidneys 9.6424 1.6131 6.8770 1.0099 3.8752 1.6179 lungs 12.9714 2.7540 8.4426 1.9117 4.3379 3.9596 small intestines 1.9641 0.1853 1.5192 0.2815 1.2201 0.3708 large intestines 1.1570 0.1960 0.5629 0.3460 0.6744 0.2893 brain 0.6536 0.2639 0.3247 0.0633 0.0290 0.0219 bladder 1.6996 0.7289 0.8092 0.2576 1.5234 2.6761 spleen 24.0497 5.3531 37.1540 0.1801 65.9117 13.1934 stomach 2.3704 0.3085 1.5867 0.2853 2.5322 1.4903 pancreas 2.2821 0.9761 2.1579 0.8408 0.4455 0.3936 bone (femur + joint) 2.7487 0.6608 2.7705 0.0730 3.8533 0.7991 thyroids 9.6295 8.0396 5.7426 3.0938 -4.6044 2.5708 tail 8.0722 6.2766 6.4201 2.1693 25.4744 20.7518

[0198] Table 3. Organ distribution of 225Ac complexes following intravenous injection in mice. Adult C57BL / 6 mice were injected with [225Ac(macropa)]+, [225Ac(DOTA)]-, or 225Ac(NO3)3 and sacrificed after 15 min, 1 h, or 5 h. Values for each time point are given as % ID / g (n=3) using energy window C (400-480 keV). Organ 15 min SD 1 h SD 5 h SD 2026249088  09 Oct 2026 [225Ac(macropa)]+ blood 6.49 4.64 0.54 0.55 0.04 0.03 urine 2387.66 1987.77 641.63 49.58 22.27 8.14 feces 1.26 2.00 0.69 0.50 5.27 2.17 heart 2.87 1.51 0.23 0.97 0.28 0.84 liver 2.72 0.61 1.08 0.45 0.55 0.08 kidneys 33.46 5.62 17.38 21.12 1.07 0.37 lungs 7.55 3.24 0.84 0.62 0.15 0.14 small intestines 3.46 2.44 1.62 0.76 0.42 0.28 large intestines 3.02 1.11 0.79 0.51 0.68 0.17 brain 0.17 0.10 0.23 0.13 -0.01 0.08 bladder 64.68 45.85 9.00 3.35 8.52 10.72 spleen 3.79 2.96 0.48 1.92 0.43 0.14 stomach 3.45 1.29 0.17 0.77 0.13 0.23 pancreas 3.00 2.21 0.43 1.01 0.13 0.29 bone (femur + joint) 3.74 1.27 0.70 0.36 0.08 0.16 thyroids -6.46 66.56 8.34 11.63 19.89 30.96 tail 11.75 0.66 2.57 1.39 0.28 0.10 [225Ac(DOTA)] — blood 7.2941 4.1461 0.1102 0.0707 - - urine 2691.0615 1906.4694 177.6788 168.4716 - - feces 1.5693 1.8307 0.4091 0.4652 - - heart 2.5579 2.0110 0.2857 0.2702 - - liver 2.9046 0.8757 0.2841 0.2157 - - kidneys 40.4489 10.8186 1.4787 0.7053 - - lungs 7.3872 1.9528 0.2551 0.1695 - - small intestines 3.8916 2.4605 2.0201 2.4443 - - large intestines 3.8419 1.8882 0.1381 0.2122 - - 2026249088  09 Oct 2026 brain 0.1588 0.0692 0.0380 0.0968 - - bladder 76.0987 42.8592 6.9149 4.5152 - - spleen 1.5598 1.6847 0.2228 0.4642 - - stomach 3.2425 2.1465 0.1720 0.2911 - - pancreas 1.0290 1.1339 0.1730 0.1437 - - bone (femur + joint) 4.4224 1.8431 0.5654 0.2432 - - thyroids -109.5394 150.5455 3.5247 36.1530 - - tail 13.4731 3.2236 1.0280 0.3206 - - 225AC(NO3)3 blood 42.3521 6.5376 11.3736 15.9719 2.1769 0.7500 urine 19.8282 14.9210 104.9103 130.5319 5.8548 8.2799 feces 0.4896 0.2884 0.1122 0.1587 0.8535 0.2061 heart 9.0992 3.1686 3.3464 4.3204 1.2018 0.1929 liver 24.1147 1.8809 23.6180 33.2545 54.1727 4.7696 kidneys 14.2266 4.1528 6.2070 7.2061 4.2061 1.5123 lungs 14.4797 2.7960 5.2078 7.2810 5.4923 4.6341 small intestines 2.0956 0.0803 3.5548 1.8035 1.2922 0.6032 large intestines 1.5716 0.8096 0.4366 - 1.0259 0.5032 brain 0.6755 0.2338 0.4402 0.1057 0.0430 0.0773 bladder 1.9351 2.1420 2.2929 1.3941 3.4975 5.8177 spleen 25.4263 6.0011 38.1082 - 62.2357 17.5694 stomach 2.4232 0.3667 2.3350 - 2.0358 1.6514 pancreas 2.4405 0.5887 1.8508 - 0.4643 0.3109 bone (femur + joint) 3.4560 0.9882 2.7213 - 3.5851 1.4683 thyroids 3.5934 1.5023 0.0000 - -0.4455 3.5100 tail 9.1381 7.4041 9.0877 - 28.4443 30.7841 2026249088  09 Oct 2026

[0199] In Vivo Studies of 225Ac-macropa-Tmab.

[0200] At the time points indicated in Table 4 below, an aliquot of complex in serum was removed and either directly analyzed by radio-TLC or first mixed with excess DTPA to remove any loosely-bound 225Ac. The decay-corrected values shown represent % activity associated with the complex at Rf=0 on the TLC plate after exposure to an EDTA mobile phase. Reported uncertainties (± 1 SD) were derived from spotting TLC plates in triplicate at each time point. The % intact complex remaining was not significantly different for samples subjected to the DTPA challenge versus those that were not (p > 0.05, 2-tail t-test). The results demonstrate that 225Ac remains strongly bound by macropa-Tmab in human serum over a 7-day period. Table 4. Complex stability (% intact complex remaining) of 225Ac-macropa-Tmab in human serum at 37 °C. 1 h 1 day 3 days 7 days Without DTPA Challenge 96.4 ± 0.9 99.0 ± 0.5 98.7 ± 0.6 99.2 ± 0.4 With DTPA Challenge - 91.5 ± 12 - 97.1 ± 1.6

[0201] Characterization of Eighteen-Membered Macrocyclic Ligands for Ion Chelation

[0202] Radium-223 (223Ra) is the first therapeutic alpha (a)-emitting radionuclide to be approved for clinical use in cancer patients, and is effective in erradicating bone metastases. To harness the therapeutic potential of a-particles for soft-tissue metastases, the strategy of targeted alpha-particle therapy (TAT) has emerged, whereby lethal a-emitting radionuclides are conjugated to tumor-targeting vectors using bifunctional chelators to selectively deliver cytotoxic alpha radiation to cancer cells. Actinium-225 (225Ac) was examined for use in TAT owing to its long 10-day half-life that is compatible with antibody-based targeting vectors and 4 high-energy a-emissions that are extremely lethal to cells. The 12-membered tetraaza macrocycle H4DOTA is currently the state of the art for the chelation of the 225Ac3+ ion, however, the thermodynamic stabilities of complexes of H4DOTA decrease as the ionic radius of the metal ion increases, indicating that this ligand is not optimal for chelation of the of the Ac3+ ion (the largest +3 ion on the periodic table). The macrocyclic complexes of the present technology provide a signifiant and unexpected improvement over known complexes, where the present examples (H2macropa and H2macropa-NCS; Scheme 1) illustrate the improved 225Ac bifunctional chelators according to the present technology. 2026249088  09 Oct 2026

[0203] Scheme 1. Structures of H2macropa, H2macropa-NCS (“macropa-NCS”), and macropa-(OCH2CH2)-Ph-NCS. 2026249088  09 Oct 2026 macropa-(OCH2CH2)-Ph-NCS

[0204] Previous studies have shown that macropa, for which the thermodynamic affinity for the whole lanthanide series was evaluated, is selective for the larger metal ions La3+, Pb2+, and Am3+ over the smaller Lu3+, Ca2+, and Cm3+ ions.[24-26] Without wishing to be bound by theory it was believed that macropa would effectively chelate the large Ac3+ ion. Before assessing its Ac-chelation properties, complex formation was evaluated in situ between macropa and cold La3+ and Lu3+ ions. In these studies, La3+ was used as a non-radioactive surrogate for 225Ac3+ because it is chemically similar albeit slightly smaller (1.03 A, CN 6). Complexation of the smaller Lu3+ ion (0.861 A, CN 6) by macropa was investigated to probe its size-selectivity. La3+ and Lu3+ titrations confirmed the high affinity of these metal ions for macropa at pH 7.4, consistent with the previously measured stability constants (log KLaL = 14.99, log KLuL = 8.25).

[24] The kinetic inertness of these complexes formed in situ was investigated by challenging them with an excess of either ethylenediaminetetraacetic acid (EDTA) or diethylenetriaminepentaacetic acid (DTPA) chelators that have a higher thermodynamic affinity than macropa for Lu3+ and La3+ ions.

[27] The Lu3+ ion was transchelated within 1 min upon the addition of only 10 equiv of EDTA, whereas the La3+ complex remained intact for up to 21 days in the presence of 1000 equiv of DTPA. These results demonstrate that, despite a strong thermodynamic preference for DTPA to transchelate La3+, the high level of kinetic inertness of the macropa complex inhibits this process on a detectable time scale.

[0205] The La3+ and Lu3+ complexes of macropa were isolated and their solid-state structures were elucidated by X-ray crystallography (FIGS. 1A-1D). The La3+ and Lu3+ ions reside above the 18-membered macrocycle, and the two picolinate arms are positioned on the same side of the 2026249088  09 Oct 2026 macrocycle. The coordination sphere of the Lu3+ ion is satisfied by the ten donors of macropa with both picolinate arms deprotonated; by contrast, the larger La3+ ion forms an 11-coordinate complex by the incorporation of an inner-sphere water molecule that penetrates the macrocycle. The ability of macropa to form stable 11-coordinate complexes is of particular significance because recent EXAFS studies have demonstrated that Ac3+ prefers a coordination number of 11 in aqueous solutions.[29,30]

[0206] Macropa was examined for the chelation of the larger, radioactive 225Ac3+ ion and compared to DOTA. Both ligands (59 pM) were incubated with 225Ac (26 kBq) in 0.15 M NH4OAC buffer at pH 5.5-6, and the complexation reaction was monitored by radio-TLC after 5 min. Remarkably, macropa complexed all the 225Ac after merely 5 min at RT, whereas DOTA only complexed 10% under these conditions. At 100-fold lower concentration (0.59 pM) of macropa, a L:M ratio of only 1800, radiolabeling was still complete at RT in 5 min. At this concentration, DOTA failed to form a complex with 225Ac. Taken together, these studies reveal macropa to exhibit excellent radiolabeling kinetics at ambient temperature and submicromolar ligand concentration, conditions under which DOTA fails.

[0207] The long half-life of 225Ac necessitates its stable complex retention in vivo to avoid off-target damage to normal tissues arising from the release of free 225Ac3+. Furthermore, the stability of 225Ac complexes against transmetalation and transchelation needs to be high. To determine the kinetic inertness, [225Ac(macropa)]+ was challeneged with La3+ because of the established high affinity of macropa for this metal ion. A 50-fold excess of La3+ with respect to ligand concentration was added to 225Ac-radiolabeled solutions of macropa (0.59 pM) at RT. Over 7 days, 98% of the 225Ac complex remained intact by radio-TLC, signifying that a large molar equivalent of La3+ is unable to displace 225Ac3+. The stability of [225Ac(macropa)]+ in human serum was also evaluated by radio-TLC and revealed that 225Ac3+ remains complexed by macropa for at least 8 days.

[0208] Evaluation of the Biodistribution of [225Ac(macropa)]+ Complexes

[0209] The in vivo stability [225Ac(macropa)]+ was examined by comparing its biodistribution to those of 225Ac(NO3)3 and [225Ac(DOTA)]-. C57BL / 6 mice were injected via tail vein with 10-50 kBq of each radiometal complex and were sacrificed after 15 min, 1 h, or 5 h. The amount of 225Ac retained in each organ was quantified by gamma counting and reported as the percent of injected dose per gram of tissue (% ID / g). The results of these studies are compiled in Tables 1-3. Inadequate stability of an 225Ac complex leading to the loss of radioisotope in 2026249088  09 Oct 2026 vivo is manifested by the accumulation of 225Ac in the liver, spleen, and bone of mice.[11,12,32] FIG. 2A demonstrates slow blood clearance and excretion, coupled to large accumulation in the liver and spleen of the uncomplexed 225Ac(NO3)3. The biodistribution profile of [225Ac(macropa)]+ (FIG. 3B) differs markedly from that of 225Ac(NO3)3. [225Ac(macropa)]+ was rapidly cleared from mice, with very little activity measured in blood by 1 h post injection. Most of the injected dose was renally excreted and subsequently detected in the urine, demonstrating the moderate kidney and bladder uptake of [225Ac(macropa)]+ observed in mice at 15 min and 1 h post injection. Of significance, [225Ac(macropa)]+ did not accumulate in any organ over the time course of the study, indicating that the complex does not release free 225Ac3+ in vivo. Its biodistribution profile was similar to that of [225Ac(DOTA)]- (FIG. 3C), which has been previously shown to retain 225Ac3+ in vivo.[7]

[0210] Synthesis and Characterization of [225Ac(macropa)]+ TAT Complexes

[0211] Due to the inherent stability of the [225Ac(macropa)]+ complexes, macropa was incorporated into into tumor-targeting constructs. To facilitate its conjugation, a reactive isothiocyanate functional group was installed onto one of the picolinate arms of macropa to give the novel bifunctional ligand macropa-NCS (Scheme 1). As illustrated in vide supra, macropa-NCS was synthesized over 8 steps and characterized by conventional techniques. For one tumor-targeting construct, macropa-NCS was s conjugated to trastuzumab (Tmab), an FDA-approved monoclonal antibody that targets the human epidermal growth factor receptor 2 (HER2) in breast and other cancers.

[33] With a biological half-life of several weeks,[34,35] Tmab is an ideal vector to shuttle the long-lived 225Ac radionuclide to tumor cells. 225Ac-macropa-Tmab displayed excellent stability in human serum at 37 °C; after 7 days, >99% of the complex remained intact (Table 4). Together, these results highlight the efficacy of macropa as a chelator for 225Ac in antibody constructs as well as other cancer-targeted constructs.

[0212] REFERENCES: 7. M. R. McDevitt, D. Ma, L. T. Lai, J. Simon, P. Borchardt, R. K. Frank, K. Wu, V. Pellegrini, M. J. Curcio, M. Miederer, et al., Science 2001, 294, 1537. 11. I. A. Davis, K. A. Glowienka, R. A. Boll, K. A. Deal, M. W. Brechbiel, M. Stabin, P. N. Bochsler, S. Mirzadeh, S. J. Kennel, Nucl. Med. Biol. 1999, 26, 581. 12. K. A. Deal, I. A. Davis, S. Mirzadeh, S. J. Kennel, M. W. Brechbiel, J. Med. Chem. 1999, 42, 2988. 2026249088  09 Oct 2026 24. A. Roca-Sabio, M. Mato-Iglesias, D. Esteban-Gomez, E. Toth, A. de Blas, C. Platas-Iglesias, T. Rodriguez-Blas, J. Am. Chem. Soc. 2009, 131, 3331. 25. R. Ferreiros-Martmez, D. Esteban-Gomez, E. Toth, A. de Blas, C. Platas-Iglesias, T. Rodriguez-Blas, Inorg. Chem. 2011, 50, 3772. 26. M. P. Jensen, R. Chiarizia, I. A. Shkrob, J. S. Ulicki, B. D. Spindler, D. J. Murphy, M. Hossain, A. Roca-Sabio, C. Platas-Iglesias, A. de Blas, et al., Inorg. Chem. 2014, 53, 6003. 27. A. E. Martell, R. M. Smith, Critical Stability Constants: Vol. 1, Plenum Press, New York; London, 1974. 29. M. G. Ferrier, E. R. Batista, J. M. Berg, E. R. Birnbaum, J. N. Cross, J. W. Engle, H. S. La Pierre, S. A. Kozimor, J. S. Lezama Pacheco, B. W. Stein, et al., Nat. Commun. 2016, 7, 12312. 30. M. G. Ferrier, B. W. Stein, E. R. Batista, J. M. Berg, E. R. Birnbaum, J. W. Engle, K. D. John, S. A. Kozimor, J. S. Lezama Pacheco, L. N. Redman, ACS Cent. Sci. 2017, 3, 176. 32. G. J. Beyer, R. Bergmann, K. Schomacker, F. Rosch, G. Schafer, E. V Kulikov, A. F. Novgorodov, Isot. Isot. Environ. Heal. Stud. 1990, 26, 111. 33. M. M. Moasser, Oncogene 2007, 26, 6469. 34. B. Leyland-Jones, K. Gelmon, J.-P. Ayoub, A. Arnold, S. Verma, R. Dias, P. Ghahramani, J. Clin. Oncol. 2003, 21, 3965. 35. D. Leveque, L. Gigou, J. P. Bergerat, Curr. Clin. Pharmacol. 2008, 3, 51. 37. A. P. Kozikowski, F. Nan, P. Conti, J. Zhang, E. Ramadan, T. Bzdega, B. Wroblewska, J. H. Neale, S. Pshenichkin, J. T. Wroblewski, J. Med. Chem. 2001, 44, 298. 38. K. P. Maresca, S. M. Hillier, F. J. Femia, D. Keith, C. Barone, J. L. Joyal, C. N. Zimmerman, A. P. Kozikowski, J. A. Barrett, W. C. Eckelman, et al., J. Med. Chem. 2009, 52, 347. 39. S. M. Hillier, K. P. Maresca, F. J. Femia, J. C. Marquis, C. A. Foss, N. Nguyen, C. N. Zimmerman, J. A. Barrett, W. C. Eckelman, M. G. Pomper, et al., Cancer Res. 2009, 69, 6932. 40. J. A. Barrett, R. E. Coleman, S. J. Goldsmith, S. Vallabhajosula, N. A. Petry, S. Cho, T. Armor, J. B. Stubbs, K. P. Maresca, M. G. Stabin, et al., J. Nucl. Med. 2013, 54, 380. 2026249088  09 Oct 2026 41. J. Kelly, A. Amor-Coarasa, A. Nikolopoulou, D. Kim, C. Williams Jr., S. Ponnala, J. W. Babich, Eur. J. Nucl. Med. Mol. Imaging 2017, 44, 647. 42. A. Ghosh, W. D. W. Heston, J. Cell. Biochem. 2004, 91, 528. 43. M. S. Dennis, M. Zhang, Y. Gloria Meng, M. Kadkhodayan, D. Kirchhofer, D. Combs, L. A. Damico, J. Biol. Chem. 2002, 277, 35035. 44. C. E. Dumelin, S. Trussel, F. Buller, E. Trachsel, F. Bootz, Y. Zhang, L. Mannocci, S. C. Beck, M. Drumea-Mirancea, M. W. Seeliger, et al., Angew. Chem. Int. Ed. 2008, 47, 3196. 102. M. Mato-Iglesias, A. Roca-Sabio, Z. Palinkas, D. Esteban-Gomez, C. Platas-Iglesias, E. Toth, A. de Blas, T. Rodriguez-Blas, Inorg. Chem. 2008, 47, 7840-7851. 103. A. Roca-Sabio, M. Mato-Iglesias, D. Esteban-Gomez, E. Toth, A. de Blas, C. Platas-Iglesias, T. Rodriguez-Blas, J. Am. Chem. Soc. 2009, 131, 3331-3341. 104.      V. J. Gatto, G. W. Gokel, J. Am. Chem. Soc. 1984, 106, 8240-8244. 105.      E. R. Neil, M. A. Fox, R. Pal, L.-O. Palsson, B. A. O’Sullivan, D. Parker, Dalton Trans. 2015, 44, 14937-14951. 106. Z. E. A. Chamas, X. Guo, J.-L. Canet, A. Gautier, D. Boyer, R. Mahiou, Dalton Trans. 2010, 39, 7091-7097. 108.      D. T. Corson, C. F. Meares, Bioconjug. Chem. 2000, 11, 292-299. 109.       G. M. Sheldrick, Acta Crystallogr. Sect. A 2015, 71, 3-8. 110.       G. M. Sheldrick, Acta Crystallogr. Sect. A 2008, 64, 112-122. 111.      P. Muller, Crystallogr. Rev. 2009, 15, 57-83. 112. O. V Dolomanov, L. J. Bourhis, R. J. Gildea, J. A. K. Howard, H. Puschmann, J. Appl. Crystallogr. 2009, 42, 339-341. 113. J. Dilling, R. Krucken, L. Merminga, Eds., ISAC and ARIEL: The TRIUMF Radioactive Beam Facilities and the Scientific Program, Springer, Dordrecht, Netherlands, 2014. 114. J. R. Crawford, P. Kunz, H. Yang, P. Schaffer, T. J. Ruth, Appl. Radiat. Isot. 2017, 122, 222-228. 115. B. Zielinska, C. Apostolidis, F. Bruchertseifer, A. Morgenstern, Solvent Extr. Ion Exch. 2007, 25, 339-349. 2026249088  09 Oct 2026 116. V. Radchenko, J. W. Engle, J. J. Wilson, J. R. Maassen, F. M. Nortier, W. A. Taylor, E. R. Birnbaum, L. A. Hudston, K. D. John, M. E. Fassbender, J. Chromatogr. A 2015,1380, 55-63. 117. M. P. Miranda-Hernandez, E. R. Valle-Gonzalez, D. Ferreira-Gomez, N. O. Perez, L. F. Flores-Ortiz, E. Medina-Rivero, Anal. Bioanal. Chem. 2016, 408, 15231530. 118. E. W. Price, K. J. Edwards, K. E. Carnazza, S. D. Carlin, B. M. Zeglis, M. J. Adam, C. Orvig, J. S. Lewis, Nucl. Med. Biol. 2016, 43, 566-576. 119. J. Kelly, A. Amor-Coarasa, A. Nikolopoulou, D. Kim, C. Williams, S. Ponnala, J. W. Babich, Eur. J. Nucl. Med. Mol. Imaging 2017, 44, 647-661.

[0213] While certain embodiments have been illustrated and described, a person with ordinary skill in the art, after reading the foregoing specification, can effect changes, substitutions of equivalents and other types of alterations to the compounds of the present technology or salts, pharmaceutical compositions, derivatives, prodrugs, metabolites, tautomers or racemic mixtures thereof as set forth herein. Each aspect and embodiment described above can also have included or incorporated therewith such variations or aspects as disclosed in regard to any or all of the other aspects and embodiments.

[0214] The present technology is also not to be limited in terms of the particular aspects described herein, which are intended as single illustrations of individual aspects of the present technology. Many modifications and variations of this present technology can be made without departing from its spirit and scope, as will be apparent to those skilled in the art. Functionally equivalent methods within the scope of the present technology, in addition to those enumerated herein, will be apparent to those skilled in the art from the foregoing descriptions. Such modifications and variations are intended to fall within the scope of the appended claims. It is to be understood that this present technology is not limited to particular methods, reagents, compounds, compositions, labeled compounds or biological systems, which can, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only, and is not intended to be limiting. Thus, it is intended that the specification be considered as exemplary only with the breadth, scope and spirit of the present technology indicated only by the appended claims, definitions therein and any equivalents thereof.

[0215] The embodiments, illustratively described herein may suitably be practiced in the absence of any element or elements, limitation or limitations, not specifically disclosed herein. 2026249088  09 Oct 2026 Thus, for example, the terms “comprising,” “including,” “containing,” etc. shall be read expansively and without limitation. Additionally, the terms and expressions employed herein have been used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the claimed technology. Additionally, the phrase “consisting essentially of” will be understood to include those elements specifically recited and those additional elements that do not materially affect the basic and novel characteristics of the claimed technology. The phrase “consisting of” excludes any element not specified.

[0216] In addition, where features or aspects of the disclosure are described in terms of Markush groups, those skilled in the art will recognize that the disclosure is also thereby described in terms of any individual member or subgroup of members of the Markush group. Each of the narrower species and subgeneric groupings falling within the generic disclosure also form part of the invention. This includes the generic description of the invention with a proviso or negative limitation removing any subject matter from the genus, regardless of whether or not the excised material is specifically recited herein.

[0217] As will be understood by one skilled in the art, for any and all purposes, particularly in terms of providing a written description, all ranges disclosed herein also encompass any and all possible subranges and combinations of subranges thereof. Any listed range can be easily recognized as sufficiently describing and enabling the same range being broken down into at least equal halves, thirds, quarters, fifths, tenths, etc. As a non-limiting example, each range discussed herein can be readily broken down into a lower third, middle third and upper third, etc. As will also be understood by one skilled in the art all language such as “up to,” “at least,” “greater than,” “less than,” and the like, include the number recited and refer to ranges which can be subsequently broken down into subranges as discussed above. Finally, as will be understood by one skilled in the art, a range includes each individual member.

[0218] All publications, patent applications, issued patents, and other documents (for example, journals, articles and / or textbooks) referred to in this specification are herein incorporated by reference as if each individual publication, patent application, issued patent, or other document was specifically and individually indicated to be incorporated by reference in its entirety. Definitions that are contained in text incorporated by reference are excluded to the extent that they contradict definitions in this disclosure. 2026249088  09 Oct 2026

[0219] The present technology may include, but is not limited to, the features and combinations of features recited in the following lettered paragraphs, it being understood that the following paragraphs should not be interpreted as limiting the scope of the claims as appended hereto or mandating that all such features must necessarily be included in such claims: A. A compound of Formula I or a pharmaceutically acceptable salt thereof, wherein Z1 is H or -X1-W2 Z2 is OH or NH-W3 Z3 is H or W7; a is 0 or 1; X1 is O, NH, or S; W2 and W3 are each independently H, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl, heteroaryl, -CH2CH2-(OCH2CH2)w-R’ where w is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, or -CH2CH2-(OCH2CH2)x-OR’ where x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, each of which may optionally be substituted with one or more of halo, -N3, -OR’, -CH2CH2-(OCH2CH2)y-R’ where y is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, -CH2CH2-(OCH2CH2)z-OR’ where z is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, -SR’, -OC(O)R’, -C(O)OR’, -C(S)OR’, -S(O)R’, -SO2R’, -SO2(OR’), -SO2NR’2, -P(O)(OR’)2, -P(O)R’(OR’), -P(O)R’2, -CN, -OCN, -SCN, -NCO, -NCS, -NR’-NH2, -N=C=N-R’, -SO2Cl, -C(O)Cl, or an epoxide group; W5 and W7 are each independently OH, NH2, SH, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl, heteroaryl, -CH2CH2-(OCH2CH2)w-R’ where w is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, or -CH2CH2-(OCH2CH2)x-OR’ where x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, each of which may optionally be substituted with one or more of halo, -N3, -OR’, -CH2CH2-(OCH2CH2)yx-R’ where y is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, -CH2CH2-(OCH2CH2)z-OR’ where z is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, -SR’, -OC(O)R’, -C(O)OR’, -C(S)OR’, -S(O)R’, -SO2R’, -SO2(OR’), - 2026249088  09 Oct 2026 SO2NR’2, -P(O)(OR’)2, -P(O)R’(OR’), -P(O)R’2, -CN, -OCN, -SCN, -NCO, -NCS, -NR’-NH2, -N=C=N-R’, -SO2Cl, -C(O)Cl, or an epoxide group; and R’ is independently at each occurance H, halo, -N3, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C5-C8 cycloalkenyl, C2-C6 alkynyl, C8-C10 cycloalkynyl, C5-C6 aryl, heterocyclyl, or heteroaryl. B. The compound of Paragraph A, wherein the compound is of Formula III or a pharmaceutically acceptable salt thereof. C. The compound of Paragraph A or Paragraph B, wherein the compound is or pharmaceutically acceptable salt thereof. D. The compound of Paragraph A, wherein the compound of Formula I is of Formula VI or a pharmaceutically acceptable salt thereof. E. The compound of Paragraph A, wherein the compound of Formula I is of Formula IX 2026249088  09 Oct 2026 or a pharmaceutically acceptable salt thereof. F. The compound of Paragraph A, wherein the compound of Formula I is of Formula XII (XII) or a pharmaceutically acceptable salt thereof. G. A compound of Formula IA M1 is an alpha-emitting radionuclide; Z1 is H or -X1-W2 Z2 is OH or NH-W3 Z3 is H or W7; a is 0 or 1; X1 is O, NH, or S; W2 and W3 are each independently H, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl, heteroaryl, -CH2CH2-(OCH2CH2)w-R’ where w is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, or -CH2CH2-(OCH2CH2)x-OR’ where x is 1, 2, 3, 4, 5, 6, 7, 8, 9, 2026249088  09 Oct 2026 or 10, each of which may optionally be substituted with one or more of halo, -N3, -OR’, -CH2CH2-(OCH2CH2)y-R’ where y is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, -CH2CH2-(OCH2CH2)z-OR’ where z is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, -SR’, -OC(O)R’, -C(O)OR’, -C(S)OR’, -S(O)R’, -SO2R’, -SO2(OR’), -SO2NR’2, -P(O)(OR’)2, -P(O)R’(OR’), -P(O)R’2, -CN, -OCN, -SCN, -NCO, -NCS, -NR’-NH2, -N=C=N-R’, -SO2Cl, -C(O)Cl, or an epoxide group; W5 and W7 are each independently OH, NH2, SH, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl, heteroaryl, -CH2CH2-(OCH2CH2)w-R’ where w is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, or -CH2CH2-(OCH2CH2)x-OR’ where x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, each of which may optionally be substituted with one or more of halo, -N3, -OR’, -CH2CH2-(OCH2CH2)yx-R’ where y is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, -CH2CH2-(OCH2CH2)z-OR’ where z is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, -SR’, -OC(O)R’, -C(O)OR’, -C(S)OR’, -S(O)R’, -SO2R’, -SO2(OR’), -SO2NR’2, -P(O)(OR’)2, -P(O)R’(OR’), -P(O)R’2, -CN, -OCN, -SCN, -NCO, -NCS, -NR’-NH2, -N=C=N-R’, -SO2Cl, -C(O)Cl, or an epoxide group; and R’ is independently at each occurance H, halo, -N3, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C5-C8 cycloalkenyl, C2-C6 alkynyl, C8-C10 cycloalkynyl, C5-C6 aryl, heterocyclyl, or heteroaryl. H. The compound of Paragraph G, wherein M1 is actinium-225 (225Ac3+), radium-223 (233Ra2+), bismuth-213 (213Bi3+), lead-212 (212Pb2+ and / or 212Pb4+), terbium-149 (149Tb3+), fermium-255 (255Fm3+), thorium-227 (227Th4+), thorium-226 (226Th4+), astatine-211 (211At+), astatine-217 (217At+), or uranium-230. I. The compound of Paragraph G or Paragraph H, wherein the compound of Formula I is of Formula IV or a pharmaceutically acceptable salt thereof, wherein M2 is an alpha-emitting radionuclide. 2026249088  09 Oct 2026 J. The compound of Paragraph I, wherein M2 is actinium-225 (225Ac3+), radium-223 (233Ra2+), bismuth-213 (213Bi3+), lead-212 (212Pb2+ and / or 212Pb4+), terbium-149 (149Tb3+), fermium-255 (255Fm3+), thorium-227 (227Th4+), thorium-226 (226Th4+), astatine-211 (211At+), astatine-217 (217At+), or uranium-230. K. The compound of Paragraph I, wherein the compound is or a pharmaceutically acceptable salt thereof. L. The compound of Paragraph K, wherein M2 is actinium-225 (225Ac3+), radium-223 (233Ra2+), bismuth-213 (213Bi3+), lead-212 (212Pb2+ and / or 212Pb4+), terbium-149 (149Tb3+), fermium-255 (255Fm3+), thorium-227 (227Th4+), thorium-226 (226Th4+), astatine-211 (211At+), astatine-217 (217At+), or uranium-230. M. The compound of Paragraph G or Paragraph H, wherein the compound of Formula IA is of Formula VIII or a pharmaceutically acceptable salt thereof, wherein M3 is an alpha-emitting radionuclide. N. The compound of Paragraph M, wherein M3 is actinium-225 (225Ac3+), radium-223 (233Ra2+), bismuth-213 (213Bi3+), lead-212 (212Pb2+ and / or 212Pb4+), terbium-149 (149Tb3+), fermium-255 (255Fm3+), thorium-227 (227Th4+), thorium-226 (226Th4+), astatine-211 (211At+), astatine-217 (217At+), or uranium-230. 2026249088  09 Oct 2026 O. The compound of Paragraph G or Paragraph H, wherein the compound of Formula IA is of Formula X or a pharmaceutically acceptable salt thereof, wherein M4 is an alpha-emitting radionuclide. P. The compound of Paragraph O, wherein M4 is actinium-225 (225Ac3+), radium-223 (233Ra2+), bismuth-213 (213Bi3+), lead-212 (212Pb2+ and / or 212Pb4+), terbium-149 (149Tb3+), fermium-255 (255Fm3+), thorium-227 (227Th4+), thorium-226 (226Th4+), astatine-211 (211At+), astatine-217 (217At+), or uranium-230. Q. The compound of Paragraph G or Paragraph H, wherein the compound of Formula IA is of Formula XIII W7 (XIII) or a pharmaceutically acceptable salt thereof, wherein M5 is an alpha-emitting radionuclide. R. The compound of Paragraph Q, wherein M5 is actinium-225 (225Ac3+), radium-223 (233Ra2+), bismuth-213 (213Bi3+), lead-212 (212Pb2+ and / or 212Pb4+), terbium-149 (149Tb3+), fermium-255 (255Fm3+), thorium-227 (227Th4+), thorium-226 (226Th4+), astatine-211 (211At+), astatine-217 (217At+), or uranium-230. S. A targeting compound of Formula II 2026249088  09 Oct 2026 Z3 (II) or a pharmaceutically acceptable salt thereof, wherein M1 is an alpha-emitting radionuclide; Z1 is H or -L3-R22 Z2 is OH or NH-L4-R24 Z3 is H or -L6-R28; a is 0 or 1; X1 is O, NH, or S; L3, L4, L5, and L6 are independently at each occurence a bond or a linker group; and R22, R24, R26, and R28 each independently comprises an antibody, antibody fragment (e.g., an antigen-binding fragment), a binding moiety, a binding peptide, a binding polypeptide (such as a selective targeting oligopeptide containing up to 50 amino acids), a binding protein, an enzyme, a nucleobase-containing moiety (such as an oligonucleotide, DNA or RNA vector, or aptamer), or a lectin. T. The targeting compound of Paragraph S, wherein M1 is actinium-225 (225Ac3+), radium-223 (233Ra2+), bismuth-213 (213Bi3+), lead-212 (212Pb2+ and / or 212Pb4+), terbium-149 (149Tb3+), fermium-255 (255Fm3+), thorium-227 (227Th4+), thorium-226 (226Th4+), astatine-211 (211At+), astatine-217 (217At+), or uranium-230. U. The targeting compound of Paragraph S or Paragraph T,wherein R22, R24, R26, and R28 each independently comprise belimumab, Mogamulizumab, Blinatumomab, Ibritumomab tiuxetan, Obinutuzumab, Ofatumumab, Rituximab, Inotuzumab ozogamicin, Moxetumomab pasudotox, Brentuximab vedotin, Daratumumab, Ipilimumab, Cetuximab, Necitumumab, Panitumumab, Dinutuximab, Pertuzumab, Trastuzumab, Trastuzumab emtansine, Siltuximab, Cemiplimab, Nivolumab, Pembrolizumab, Olaratumab, Atezolizumab, Avelumab, Durvalumab, Capromab pendetide, Elotuzumab, Denosumab, Ziv-aflibercept, Bevacizumab, Ramucirumab, Tositumomab, Gemtuzumab 2026249088  09 Oct 2026 ozogamicin, Alemtuzumab, Cixutumumab, Girentuximab, Nimotuzumab, Catumaxomab, Etaracizumab, an antigen-binding fragment of any thereof, a prostate specific membrane antigen (“PSMA”) binding peptide, a somatostatin receptor agonist, a bombesin receptor agonist, a seprase binding compound, or a binding fragement of any thereof. V. The targeting compound of any one of Paragraphs S-U, wherein the targeting compound of Formula II is of Formula V or a pharmaceutically acceptable salt thereof, wherein M2 is an alpha-emitting radionuclide. W. The targeting compound of Paragraph V, wherein M2 is actinium-225 (225Ac3+), radium-223 (233Ra2+), bismuth-213 (213Bi3+), lead-212 (212Pb2+ and / or 212Pb4+), terbium-149 (149Tb3+), fermium-255 (255Fm3+), thorium-227 (227Th4+), thorium-226 (226Th4+), astatine-211 (211At+), astatine-217 (217At+), or uranium-230. X. The targeting compound of any one of Paragraphs S-U, wherein the targeting compound of Formula II is of Formula VIII or a pharmaceutically acceptable salt thereof, wherein M3 is an alpha-emitting radionuclide. Y. The targeting compound of Paragraph X, wherein M3 is actinium-225 (225Ac3+), radium-223 (233Ra2+), bismuth-213 (213Bi3+), lead-212 (212Pb2+ and / or 212Pb4+), terbium-149 (149Tb3+), 2026249088  09 Oct 2026 fermium-255 (255Fm3+), thorium-227 (227Th4+), thorium-226 (226Th4+), astatine-211 (211At+), astatine-217 (217At+), or uranium-230. Z. The targeting compound of any one of Paragraphs S-U, wherein the targeting compound of Formula II is of Formula XI R26 (XI) or a pharmaceutically acceptable salt thereof, wherein M4 an alpha-emitting radionuclide. AA. The targeting compound of Paragraph Z, wherein M4 is actinium-225 (225Ac3+), radium-223 (233Ra2+), bismuth-213 (213Bi3+), lead-212 (212Pb2+ and / or 212Pb4+), terbium-149 (149Tb3+), fermium-255 (255Fm3+), thorium-227 (227Th4+), thorium-226 (226Th4+), astatine-211 (211At+), astatine-217 (217At+), or uranium-230. AB. The targeting compound of any one of Paragraphs S-U, wherein the targeting compound of Formula II is of Formula XIV (XIV) or a pharmaceutically acceptable salt thereof, wherein M5 is an alpha-emitting radionuclide. AC. The targeting compound of Paragraph AB, wherein M5 is actinium-225 (225Ac3+), radium-223 (233Ra2+), bismuth-213 (213Bi3+), lead-212 (212Pb2+ and / or 212Pb4+), terbium-149 (149Tb3+), fermium-255 (255Fm3+), thorium-227 (227Th4+), thorium-226 (226Th4+), astatine-211 (211At+), astatine-217 (217At+), or uranium-230. 2026249088  09 Oct 2026 AD. A modified antibody, modified antibody fragment, or modified binding peptide comprising a linkage arising from conjugation of a compound of Formula I Z1 is H or -X1-W2 Z2 is OH or NH-W3 Z3 is H or W7; a is 0 or 1; X1 is O, NH, or S; W2 and W3 are each independently H, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl, heteroaryl, -CH2CH2-(OCH2CH2)w-R’ where w is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, or -CH2CH2-(OCH2CH2)x-OR’ where x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, each of which may optionally be substituted with one or more of halo, -N3, -OR’, -CH2CH2-(OCH2CH2)y-R’ where y is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, -CH2CH2-(OCH2CH2)z-OR’ where z is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, -SR’, -OC(O)R’, -C(O)OR’, -C(S)OR’, -S(O)R’, -SO2R’, -SO2(OR’), -SO2NR’2, -P(O)(OR’)2, -P(O)R’(OR’), -P(O)R’2, -CN, -OCN, -SCN, -NCO, -NCS, -NR’-NH2, -N=C=N-R’, -SO2Cl, -C(O)Cl, or an epoxide group; W5 and W7 are each independently OH, NH2, SH, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl, heteroaryl, -CH2CH2-(OCH2CH2)w-R’ where w is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, or -CH2CH2-(OCH2CH2)x-OR’ where x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, each of which may optionally be substituted with one or more of halo, -N3, -OR’, -CH2CH2-(OCH2CH2)yx-R’ where y is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, -CH2CH2-(OCH2CH2)z-OR’ where z is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, -SR’, -OC(O)R’, -C(O)OR’, -C(S)OR’, -S(O)R’, -SO2R’, -SO2(OR’), -SO2NR’2, -P(O)(OR’)2, -P(O)R’(OR’), -P(O)R’2, -CN, -OCN, -SCN, -NCO, -NCS, -NR’-NH2, -N=C=N-R’, -SO2Cl, -C(O)Cl, or an epoxide group; and 2026249088  09 Oct 2026 R’ is independently at each occurance H, halo, -N3, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C5-C8 cycloalkenyl, C2-C6 alkynyl, C8-C10 cycloalkynyl, C5-C6 aryl, heterocyclyl, or heteroaryl. AE. The modified antibody, modified antibody fragment, or modified binding peptide of Paragraph AD, wherein the antibody comprises belimumab, Mogamulizumab, Blinatumomab, Ibritumomab tiuxetan, Obinutuzumab, Ofatumumab, Rituximab, Inotuzumab ozogamicin, Moxetumomab pasudotox, Brentuximab vedotin, Daratumumab, Ipilimumab, Cetuximab, Necitumumab, Panitumumab, Dinutuximab, Pertuzumab, Trastuzumab, Trastuzumab emtansine, Siltuximab, Cemiplimab, Nivolumab, Pembrolizumab, Olaratumab, Atezolizumab, Avelumab, Durvalumab, Capromab pendetide, Elotuzumab, Denosumab, Ziv-aflibercept, Bevacizumab, Ramucirumab, Tositumomab, Gemtuzumab ozogamicin, Alemtuzumab, Cixutumumab, Girentuximab, Nimotuzumab, Catumaxomab, or Etaracizumab. AF. The modified antibody, modified antibody fragment, or modified binding peptide of Paragraph AD or Paragraph AE, wherein the antibody fragment comprises an antigenbinding fragment of belimumab, Mogamulizumab, Blinatumomab, Ibritumomab tiuxetan, Obinutuzumab, Ofatumumab, Rituximab, Inotuzumab ozogamicin, Moxetumomab pasudotox, Brentuximab vedotin, Daratumumab, Ipilimumab, Cetuximab, Necitumumab, Panitumumab, Dinutuximab, Pertuzumab, Trastuzumab, Trastuzumab emtansine, Siltuximab, Cemiplimab, Nivolumab, Pembrolizumab, Olaratumab, Atezolizumab, Avelumab, Durvalumab, Capromab pendetide, Elotuzumab, Denosumab, Ziv-aflibercept, Bevacizumab, Ramucirumab, Tositumomab, Gemtuzumab ozogamicin, Alemtuzumab, Cixutumumab, Girentuximab, Nimotuzumab, Catumaxomab, or Etaracizumab. AG. The modified antibody, modified antibody fragment, or modified binding peptide of any one of Paragraphs AD-AF, wherein the binding peptide comprises comprises a prostate specific membrane antigen (“PSMA”) binding peptide, a somatostatin receptor agonist, a bombesin receptor agonist, a seprase binding compound, or a binding fragement thereof. AH. The modified antibody, modified antibody fragment, or modified binding peptideof any one of Paragraphs AD-AG, wherein the compound of Formula I is of Formula III 2026249088  09 Oct 2026 or a pharmaceutically acceptable salt thereof. AI. The modified antibody, modified antibody fragment, or modified binding peptideof any one of Paragraphs AD-AH, wherein the linkage is a thiocyante linkage; wherein the thiocyanate linkage arises from conjugation of the compound with the antibody, antibody fragment, or binding peptide; and wherein the compound is SCN or pharmaceutically acceptable salt thereof. AJ. The modified antibody, modified antibody fragment, or modified binding peptideof any one of Paragraphs AD-AG, wherein the compound of Formula I is of Formula VI or a pharmaceutically acceptable salt thereof. AK. The modified antibody, modified antibody fragment, or modified binding peptideof any one of Paragraphs AD-AG, wherein the compound of Formula I is of Formula IX 2026249088  09 Oct 2026 or a pharmaceutically acceptable salt thereof. AL. The modified antibody, modified antibody fragment, or modified binding peptideof any one of Paragraphs AD-AG, wherein the compound of Formula I is of Formula XII (XII) or a pharmaceutically acceptable salt thereof. AM. A modified antibody, modified antibody fragment, or modified binding peptide comprising a linkage arising from conjugation of a compound of Formula IA (IA) or a pharmaceutically acceptable salt thereof, with an antibody, antibody fragment, or binding peptide, wherein M1 is an alpha-emitting radionuclide; Z1 is H or -X1-W2 Z2 is OH or NH-W3 Z3 is H or W7; a is 0 or 1; X1 is O, NH, or S; 2026249088  09 Oct 2026 W2 and W3 are each independently H, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl, heteroaryl, -CH2CH2-(OCH2CH2)w-R’ where w is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, or -CH2CH2-(OCH2CH2)x-OR’ where x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, each of which may optionally be substituted with one or more of halo, -N3, -OR’, -CH2CH2-(OCH2CH2)y-R’ where y is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, -CH2CH2-(OCH2CH2)z-OR’ where z is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, -SR’, -OC(O)R’, -C(O)OR’, -C(S)OR’, -S(O)R’, -SO2R’, -SO2(OR’), -SO2NR’2, -P(O)(OR’)2, -P(O)R’(OR’), -P(O)R’2, -CN, -OCN, -SCN, -NCO, -NCS, -NR’-NH2, -N=C=N-R’, -SO2Cl, -C(O)Cl, or an epoxide group; W5 and W7 are each independently OH, NH2, SH, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl, heteroaryl, -CH2CH2-(OCH2CH2)w-R’ where w is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, or -CH2CH2-(OCH2CH2)x-OR’ where x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, each of which may optionally be substituted with one or more of halo, -N3, -OR’, -CH2CH2-(OCH2CH2)yx-R’ where y is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, -CH2CH2-(OCH2CH2)z-OR’ where z is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, -SR’, -OC(O)R’, -C(O)OR’, -C(S)OR’, -S(O)R’, -SO2R’, -SO2(OR’), -SO2NR’2, -P(O)(OR’)2, -P(O)R’(OR’), -P(O)R’2, -CN, -OCN, -SCN, -NCO, -NCS, -NR’-NH2, -N=C=N-R’, -SO2Cl, -C(O)Cl, or an epoxide group; and R’ is independently at each occurance H, halo, -N3, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C5-C8 cycloalkenyl, C2-C6 alkynyl, C8-C10 cycloalkynyl, C5-C6 aryl, heterocyclyl, or heteroaryl. AN. The modified antibody, modified antibody fragment, or modified binding peptide of Paragraph AM, wherein M1 is actinium-225 (225Ac3+), radium-223 (233Ra2+), bismuth-213 (213Bi3+), lead-212 (212Pb2+ and / or 212Pb4+), terbium-149 (149Tb3+), fermium-255 (255Fm3+), thorium-227 (227Th4+), thorium-226 (226Th4+), astatine-211 (211At+), astatine-217 (217At+), or uranium-230. AO. The modified antibody, modified antibody fragment, or modified binding peptide of Paragraph AM or Paragraph AN, wherein the antibody comprises belimumab, Mogamulizumab, Blinatumomab, Ibritumomab tiuxetan, Obinutuzumab, Ofatumumab, Rituximab, Inotuzumab ozogamicin, Moxetumomab pasudotox, Brentuximab vedotin, Daratumumab, Ipilimumab, Cetuximab, Necitumumab, Panitumumab, Dinutuximab, 2026249088  09 Oct 2026 Pertuzumab, Trastuzumab, Trastuzumab emtansine, Siltuximab, Cemiplimab, Nivolumab, Pembrolizumab, Olaratumab, Atezolizumab, Avelumab, Durvalumab, Capromab pendetide, Elotuzumab, Denosumab, Ziv-aflibercept, Bevacizumab, Ramucirumab, Tositumomab, Gemtuzumab ozogamicin, Alemtuzumab, Cixutumumab, Girentuximab, Nimotuzumab, Catumaxomab, or Etaracizumab. AP. The modified antibody, modified antibody fragment, or modified binding peptide of any one of Paragraphs AM-AO, wherein the antibody fragment comprises an antigen-binding fragment of belimumab, Mogamulizumab, Blinatumomab, Ibritumomab tiuxetan, Obinutuzumab, Ofatumumab, Rituximab, Inotuzumab ozogamicin, Moxetumomab pasudotox, Brentuximab vedotin, Daratumumab, Ipilimumab, Cetuximab, Necitumumab, Panitumumab, Dinutuximab, Pertuzumab, Trastuzumab, Trastuzumab emtansine, Siltuximab, Cemiplimab, Nivolumab, Pembrolizumab, Olaratumab, Atezolizumab, Avelumab, Durvalumab, Capromab pendetide, Elotuzumab, Denosumab, Ziv-aflibercept, Bevacizumab, Ramucirumab, Tositumomab, Gemtuzumab ozogamicin, Alemtuzumab, Cixutumumab, Girentuximab, Nimotuzumab, Catumaxomab, or Etaracizumab. AQ. The modified antibody, modified antibody fragment, or modified binding peptide of any one of Paragraphs AM-AP, wherein the binding peptide comprises a prostate specific membrane antigen (“PSMA”) binding peptide, a somatostatin receptor agonist, a bombesin receptor agonist, a seprase binding compound, or a binding fragement thereof. AR. The modified antibody, modified antibody fragment, or modified binding peptide of any one of Paragraphs AM-AQ, wherein the compound of Formula I is of Formula IV (IV) or a pharmaceutically acceptable salt thereof, wherein M2 is an alpha-emitting radionuclide. AS. The modified antibody, modified antibody fragment, or modified binding peptide of Paragraph AR, wherein M2 is actinium-225 (225Ac3+), radium-223 (233Ra2+), bismuth-213 (213Bi3+), lead-212 (212Pb2+ and / or 212Pb4+), terbium-149 (149Tb3+), fermium-255 2026249088  09 Oct 2026 (255Fm3+), thorium-227 (227Th4+), thorium-226 (226Th4+), astatine-211 (211At+), astatine-217 (217At+), or uranium-230. AT. The modified antibody, modified antibody fragment, or modified binding peptide of Paragraph AR, wherein the linkage is a thiocyante linkage; wherein the thiocyanate linkage arises from conjugation of the compound with the antibody, antibody fragment, or binding peptide; and wherein the compound is AU. The modified antibody, modified antibody fragment, or modified binding peptide of Paragraph AT, wherein M2 is actinium-225 (225Ac3+), radium-223 (233Ra2+), bismuth-213 (213Bi3+), lead-212 (212Pb2+ and / or 212Pb4+), terbium-149 (149Tb3+), fermium-255 (255Fm3+), thorium-227 (227Th4+), thorium-226 (226Th4+), astatine-211 (211At+), astatine-217 (217At+), or uranium-230. AV. The modified antibody, modified antibody fragment, or modified binding peptide of any one of Paragraphs AM-AQ, wherein the compound of Formula IA is of Formula VIII (_ N O-7 (Z \= /    \— /    \= / 0H >nh O \ 3 W3                     (VII) or a pharmaceutically acceptable salt thereof, wherein M3 is an alpha-emitting radionuclide. AW. The modified antibody, modified antibody fragment, or modified binding peptide of Paragraph AV, wherein M3 is actinium-225 (225Ac3+), radium-223 (233Ra2+), bismuth-213 (213Bi3+), lead-212 (212Pb2+ and / or 212Pb4+), terbium-149 (149Tb3+), fermium-255 2026249088  09 Oct 2026 (255Fm3+), thorium-227 (227Th4+), thorium-226 (226Th4+), astatine-211 (211At+), astatine-217 (217At+), or uranium-230. AX. The modified antibody, modified antibody fragment, or modified binding peptide of any one of Paragraphs AM-AQ, wherein the compound of Formula IA is of Formula X or a pharmaceutically acceptable salt thereof, wherein M4 is an alpha-emitting radionuclide. AY. The modified antibody, modified antibody fragment, or modified binding peptide of Paragraph AX, wherein M4 is actinium-225 (225Ac3+), radium-223 (233Ra2+), bismuth-213 (213Bi3+), lead-212 (212Pb2+ and / or 212Pb4+), terbium-149 (149Tb3+), fermium-255 (255Fm3+), thorium-227 (227Th4+), thorium-226 (226Th4+), astatine-211 (211At+), astatine-217 (217At+), or uranium-230. AZ. The modified antibody, modified antibody fragment, or modified binding peptide of any one of Paragraphs AM-AQ, wherein the compound of Formula IA is of Formula XIII (XIII) or a pharmaceutically acceptable salt thereof, wherein M5 is an alpha-emitting radionuclide. BA. The modified antibody, modified antibody fragment, or modified binding peptide of Paragraph AZ, wherein M5 is actinium-225 (225Ac3+), radium-223 (233Ra2+), bismuth-213 (213Bi3+), lead-212 (212Pb2+ and / or 212Pb4+), terbium-149 (149Tb3+), fermium-255 (255Fm3+), thorium-227 (227Th4+), thorium-226 (226Th4+), astatine-211 (211At+), astatine-217 (217At+), or uranium-230. 2026249088  09 Oct 2026 BB. A composition comprising a pharmaceutically acceptable carrier and a compound of any one of Paragraphs A-R. BC. A composition comprising a pharmaceutically acceptable carrier and a targeting compound of any one of Paragraphs S-AC or comprising a pharmaceutically acceptable carrier and a modified antibody, modified antibody fragment, or modified binding peptide of any one of Paragraphs AD-BA. BD. A pharmaceutical composition useful in targeted radiotherapy of cancer and / or mammalian tissue overexpressing prostate specific membrane antigen (“PSMA”) in a subject, wherein the pharmaceutical composition comprises a pharmaceutically acceptable carrier and a compound of any one of Paragraphs S-AC or a modified antibody, modified antibody fragment, or modified binding peptide of any one of Paragraphs AD-BA. BE. The pharmaceutical composition of Paragraph BD, wherein the pharmaceutical composition comprises an effective amount for treating the cancer and / or mammalian tissue overexpressing PSMA of the compound or an effective amount for treating the cancer and / or mammalian tissue overexpressing PSMA of the modified antibody, modified antibody fragment, or modified binding peptide. BF. The pharmaceutical composition of Paragraph BD or Paragraph BE, where the subject suffers from a mammalian tissue expressing a somatostatin receptor, a bombesin receptor, seprase, or a combination of any two or more thereof, and / or mammalian tissue overexpressing PSMA. BG. The pharmaceutical composition of any one of Paragraphs BD-BF, wherein the subject suffers from one or more of a growth hormone producing tumor, a neuroendocrine tumor, a pituitary tumor, a vasoactive intestinal peptide-secreting tumor, a small cell carcinoma of the lung, gastric cancer tissue, pancreatic cancer tissue, a neuroblastoma, BH. The pharmaceutical composition of any one of Paragraphs BD-BG, wherein the subject suffers from one or more of a glioma, a breast cancer, an adrenal cortical cancer, a cervical carcinoma, a vulvar carcinoma, an endometrial carcinoma, a primary ovarian carcinoma, a metastatic ovarian carcinoma, a non-small cell lung cancer, a small cell lung cancer, a bladder cancer, a colon cancer, a primary gastric adenocarcinoma, a primary colorectal adenocarcinoma, a renal cell carcinoma, and a prostate cancer. 2026249088  09 Oct 2026 BI. The pharmaceutical composition of any one of Paragraphs BD-BH, wherein the pharmaceutical composition is formulated for intraveneous administration, optionally comprising sterilized water, Ringer's solution, or an isotonic aqueous saline solution. BJ. The pharmaceutical composition of any one of Paragraphs BD-BI, wherein the effective amount of the compound is from about 0.01 pg to about 10 mg of the compound per gram of the pharmaceutical composition. BK. The pharmaceutical composition of any one of Paragraphs BD-BJ, wherein the pharmaceutical composition is provided in an injectable dosage form. BL. A method of treating a subject, wherein the method comprises administering a targeting compound of any one of Paragraphs S-AC to the subject or administering a modified antibody, modified antibody fragment, or modified binding peptide of any one of Paragraphs AD-BA. BM. The method of Paragraph BL, wherein the subject suffers from cancer and / or mammalian tissue overexpressing prostate specific membrane antigen (“PSMA”) BN. The method of Paragraph BM, wherein the method comprises administering an effective amount for treating the cancer and / or mammalian tissue overexpressing PSMA of the compound or an effective amount for treating the cancer and / or mammalian tissue overexpressing PSMA of the modified antibody, modified antibody fragment, or modified binding peptide BO. The method of any one of Paragraphs BL-BN, wherein the subject suffers from a mammalian tissue expressing a somatostatin receptor, a bombesin receptor, seprase, or a combination of any two or more thereof and / or mammalian tissue overexpressing prostate specific membrane antigen (“PSMA”), when administered to a subject. BP. The method of any one of Paragraphs BL-BO, wherein the mammalian tissue comprises one or more of a growth hormone producing tumor, a neuroendocrine tumor, a pituitary tumor, a vasoactive intestinal peptide-secreting tumor, a small cell carcinoma of the lung, gastric cancer tissue, pancreatic cancer tissue, a neuroblastoma, and a metastatic cancer. BQ. The method of any one of Paragraphs BL-BP, wherein the subject suffers from one or more of a glioma, a breast cancer, an adrenal cortical cancer, a cervical carcinoma, a vulvar carcinoma, an endometrial carcinoma, a primary ovarian carcinoma, a metastatic ovarian 2026249088  09 Oct 2026 carcinoma, a non-small cell lung cancer, a small cell lung cancer, a bladder cancer, a colon cancer, a primary gastric adenocarcinoma, a primary colorectal adenocarcinoma, a renal cell carcinoma, and a prostate cancer. BR. The method of any one of Paragraphs BL-BQ, wherein the administering comprises parenteral administration. BS. The method of any one of Paragraphs BL-BR, wherein the administeringcomprises intraveneous administration. BT. The method of any one of Paragraphs BL-BS, wherein the effective amount is from about 0.1 pg to about 50 pg per kilogram of subject mass. BU. A compound comprising a first domain having a blood-protein binding moiety with low specific affinity for the blood-protein, a second domain having a tumor targeting moiety with high affinity for a tumor antigen, and a third domain having a chelator. BV. The compound of Paragraph BU, wherein the tumor antigen is PSMA, bombesin, somatostatin receptor, or seprase. BW. The compound of Paragraph BU or Paragraph BV, wherein the blood protein binding moiety has specific affinity for albumin of about 0.5-50 x 10-6M, and the tumor targeting moiety has specific affinity for the tumor antigen of about 0.5-50 x 10-9M. BX. A compound represented by the following structure / —N       N- O^\__N O_O ~ )   VoH C ° HN / HN ■ _ - “ ( HN— q >4 ANH O / -0 o—-o Al A A. JL HN N^V^N^ CO2H     A       Nn \ A X ho2c n n co2h H H or a pharmaceutically acceptable salt thereof. BY. A composition comprising the compound of Paragraph BX chelating 213Bi3+, 211At+, 233Ra2+, 212Pb2+ , or 212Pb4+. hnA 0 HN^ Vn o         rA co2h 0 OH      / —2 0^ o^ 225Ac3+ 152Dy3+ 212Bi3+, 211^3+ 217^+, 227^4+ 226^4+ 156 2026249088  09 Oct 2026 BZ. A method of treating a subject, wherein the method comprises administering a composition of Paragraph BY to the subject. CA. The method of Paragraph BZ, wherein the subject suffers from cancer and / or mammalian tissue overexpressing prostate specific membrane antigen (“PSMA”) CB. The method of Paragraph CA, wherein the method comprises administering an effective amount for treating the cancer and / or mammalian tissue overexpressing PSMA of the composition. CC. The method of any one of Paragraphs BZ-CB, wherein the subject suffers from a mammalian tissue overexpressing prostate specific membrane antigen (“PSMA”). CD. The method of any one of Paragraphs BZ-CC, wherein the mammalian tissue comprises one or more of a growth hormone producing tumor, a neuroendocrine tumor, a pituitary tumor, a vasoactive intestinal peptide-secreting tumor, a small cell carcinoma of the lung, gastric cancer tissue, pancreatic cancer tissue, a neuroblastoma, and a metastatic cancer. CE. The method of any one of Paragraphs BZ-CD, wherein the subject suffers from one or more of a glioma, a breast cancer, an adrenal cortical cancer, a cervical carcinoma, a vulvar carcinoma, an endometrial carcinoma, a primary ovarian carcinoma, a metastatic ovarian carcinoma, a non-small cell lung cancer, a small cell lung cancer, a bladder cancer, a colon cancer, a primary gastric adenocarcinoma, a primary colorectal adenocarcinoma, a renal cell carcinoma, and a prostate cancer. CF. The method of any one of Paragraphs BZ-CE, wherein the administering comprises parenteral administration. CG. The method of any one of Paragraphs BZ-CF, wherein the administeringcomprises intraveneous administration. CH. The method of any one of Paragraphs BZ-CG, wherein the effective amount is from about 0.1 pg to about 50 pg per kilogram of subject mass.

[0220] Other embodiments are set forth in the following claims, along with the full scope of equivalents to which such claims are entitled.

Claims

2026249088  09 Oct 20261. A compound of Formula I(I)or a pharmaceutically acceptable salt thereof, whereinZ1 is H or -X1-W2Z2 is OH or NH-W3Z3 is H or W7;a is 0 or 1;X1 is O, NH, or S;W2 and W3 are each independently H, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl, heteroaryl, -CH2CH2-(OCH2CH2)w-R’ where w is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, or -CH2CH2-(OCH2CH2)x-OR’ where x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, each of which may optionally be substituted with one or more of halo, -N3, -OR’, -CH2CH2-(OCH2CH2)y-R’ where y is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, -CH2CH2-(OCH2CH2)z-OR’ where z is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, -SR’, -OC(O)R’, -C(O)OR’, -C(S)OR’, -S(O)R’, -SO2R’, -SO2(OR’), -SO2NR’2, -P(O)(OR’)2, -P(O)R’(OR’), -P(O)R’2, -CN, -OCN, -SCN, -NCO, -NCS, -NR’-NH2, -N=C=N-R’, -SO2Cl, -C(O)Cl, or an epoxide group;W5 and W7 are each independently OH, NH2, SH, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl, heteroaryl, -CH2CH2-(OCH2CH2)w-R’ where w is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, or -CH2CH2-(OCH2CH2)x-OR’ where x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, each of which may optionally be substituted with one or more of halo, -N3, -OR’, -CH2CH2-(OCH2CH2)yx-R’ where y is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, -CH2CH2-(OCH2CH2)z-OR’ where z is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, -SR’, -OC(O)R’, -C(O)OR’, -C(S)OR’, -S(O)R’, -SO2R’, -SO2(OR’), -SO2NR’2, -P(O)(OR’)2, -P(O)R’(OR’), -P(O)R’2, -CN, -OCN, -SCN, -NCO, -NCS, -NR’-NH2, -N=C=N-R’, -SO2Cl, -C(O)Cl, or an epoxide group; and2026249088  09 Oct 2026R’ is independently at each occurance H, halo, -N3, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C5-C8 cycloalkenyl, C2-C6 alkynyl, C8-C10 cycloalkynyl, C5-C6 aryl, heterocyclyl, or heteroaryl.

2. The compound of claim 1, wherein the compound is of Formula III(III)or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 or claim 2, wherein the compound isor pharmaceutically acceptable salt thereof.

4. The compound of claim 1, wherein the compound of Formula I is of Formula VIor a pharmaceutically acceptable salt thereof.

5. The compound of claim 1, wherein the compound of Formula I is of Formula IX2026249088  09 Oct 2026or a pharmaceutically acceptable salt thereof.

6. The compound of claim 1, wherein the compound of Formula I is of Formula XII(XII)or a pharmaceutically acceptable salt thereof.

7. A compound of Formula IAM1 is an alpha-emitting radionuclide;Z1 is H or -X1-W2Z2 is OH or NH-W3Z3 is H or W7;a is 0 or 1;X1 is O, NH, or S;W2 and W3 are each independently H, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl,aryl, heterocyclyl, heteroaryl, -CH2CH2-(OCH2CH2)w-R’ where w is 1, 2, 3, 4, 5,6, 7, 8, 9, or 10, or -CH2CH2-(OCH2CH2)x-OR’ where x is 1, 2, 3, 4, 5, 6, 7, 8, 9,2026249088  09 Oct 2026or 10, each of which may optionally be substituted with one or more of halo, -N3, -OR’, -CH2CH2-(OCH2CH2)y-R’ where y is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, -CH2CH2-(OCH2CH2)z-OR’ where z is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, -SR’, -OC(O)R’, -C(O)OR’, -C(S)OR’, -S(O)R’, -SO2R’, -SO2(OR’), -SO2NR’2, -P(O)(OR’)2, -P(O)R’(OR’), -P(O)R’2, -CN, -OCN, -SCN, -NCO, -NCS, -NR’-NH2, -N=C=N-R’, -SO2Cl, -C(O)Cl, or an epoxide group;W5 and W7 are each independently OH, NH2, SH, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl, heteroaryl, -CH2CH2-(OCH2CH2)w-R’ where w is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, or -CH2CH2-(OCH2CH2)x-OR’ where x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, each of which may optionally be substituted with one or more of halo, -N3, -OR’, -CH2CH2-(OCH2CH2)yx-R’ where y is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, -CH2CH2-(OCH2CH2)z-OR’ where z is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, -SR’, -OC(O)R’, -C(O)OR’, -C(S)OR’, -S(O)R’, -SO2R’, -SO2(OR’), -SO2NR’2, -P(O)(OR’)2, -P(O)R’(OR’), -P(O)R’2, -CN, -OCN, -SCN, -NCO, -NCS, -NR’-NH2, -N=C=N-R’, -SO2Cl, -C(O)Cl, or an epoxide group; andR’ is independently at each occurance H, halo, -N3, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C5-C8 cycloalkenyl, C2-C6 alkynyl, C8-C10 cycloalkynyl, C5-C6 aryl, heterocyclyl, or heteroaryl.

8. The compound of claim 7, wherein M1 is actinium-225 (225Ac3+), radium-223 (233Ra2+), bismuth-213 (213Bi3+), lead-212 (212Pb2+ and / or 212Pb4+), terbium-149 (149Tb3+), fermium-255 (255Fm3+), thorium-227 (227Th4+), thorium-226 (226Th4+), astatine-211 (211At+), astatine-217 (217At+), or uranium-230.

9. The compound of claim 7 or claim 8, wherein the compound of Formula I is of Formula IV(IV)or a pharmaceutically acceptable salt thereof, wherein M2 is an alpha-emittingradionuclide.2026249088  09 Oct 202610. The compound of claim 9, wherein M2 is actinium-225 (225Ac3+), radium-223 (233Ra2+), bismuth-213 (213Bi3+), lead-212 (212Pb2+ and / or 212Pb4+), terbium-149 (149Tb3+), fermium-255 (255Fm3+), thorium-227 (227Th4+), thorium-226 (226Th4+), astatine-211 (211At+), astatine-217 (217At+), or uranium-230.

11. The compound of claim 9, wherein the compound isor a pharmaceutically acceptable salt thereof.

12. The compound of claim 11, wherein M2 is actinium-225 (225Ac3+), radium-223 (233Ra2+), bismuth-213 (213Bi3+), lead-212 (212Pb2+ and / or 212Pb4+), terbium-149 (149Tb3+), fermium-255 (255Fm3+), thorium-227 (227Th4+), thorium-226 (226Th4+), astatine-211 (211At+), astatine-217 (217At+), or uranium-230.

13. The compound of claim 7 or claim 8, wherein the compound of Formula IA is of Formula VIIIor a pharmaceutically acceptable salt thereof, wherein M3 is an alpha-emitting radionuclide.

14. The compound of claim 13, wherein M3 is actinium-225 (225Ac3+), radium-223 (233Ra2+), bismuth-213 (213Bi3+), lead-212 (212Pb2+ and / or 212Pb4+), terbium-149 (149Tb3+), fermium-255 (255Fm3+), thorium-227 (227Th4+), thorium-226 (226Th4+), astatine-211 (211At+), astatine-217 (217At+), or uranium-230.

15. The compound of claim 7 or claim 8, wherein the compound of Formula IA is of Formula X2026249088  09 Oct 2026or a pharmaceutically acceptable salt thereof, wherein M4 is an alpha-emitting radionuclide.

16. The compound of claim 15, wherein M4 is actinium-225 (225Ac3+), radium-223 (233Ra2+), bismuth-213 (213Bi3+), lead-212 (212Pb2+ and / or 212Pb4+), terbium-149 (149Tb3+), fermium-255 (255Fm3+), thorium-227 (227Th4+), thorium-226 (226Th4+), astatine-211 (211At+), astatine-217 (217At+), or uranium-230.

17. The compound of claim 7 or claim 8, wherein the compound of Formula IA is of FormulaXIII(XIII)or a pharmaceutically acceptable salt thereof, wherein M5 is an alpha-emittingradionuclide.

18. The compound of claim 17, wherein M5 is actinium-225 (225Ac3+), radium-223 (233Ra2+), bismuth-213 (213Bi3+), lead-212 (212Pb2+ and / or 212Pb4+), terbium-149 (149Tb3+), fermium-255 (255Fm3+), thorium-227 (227Th4+), thorium-226 (226Th4+), astatine-211 (211At+), astatine-217 (217At+), or uranium-230.

19. A targeting compound of Formula II2026249088  09 Oct 2026Z3(II)or a pharmaceutically acceptable salt thereof, whereinM1 is an alpha-emitting radionuclide;Z1 is H or -L3-R22Z2 is OH or NH-L4-R24Z3 is H or -L6-R28;a is 0 or 1;X1 is O, NH, or S;L3, L4, L5, and L6 are independently at each occurence a bond or a linker group; and R22, R24, R26, and R28 each independently comprises an antibody, antibody fragment (e.g., an antigen-binding fragment), a binding moiety, a binding peptide, a binding polypeptide (such as a selective targeting oligopeptide containing up to 50 amino acids), a binding protein, an enzyme, a nucleobase-containing moiety (such as an oligonucleotide, DNA or RNA vector, or aptamer), or a lectin.

20. The targeting compound of claim 19, wherein M1 is actinium-225 (225Ac3+), radium-223 (233Ra2+), bismuth-213 (213Bi3+), lead-212 (212Pb2+ and / or 212Pb4+), terbium-149 (149Tb3+), fermium-255 (255Fm3+), thorium-227 (227Th4+), thorium-226 (226Th4+), astatine-211 (211At+), astatine-217 (217At+), or uranium-230.

21. The targeting compound of claim 19 or claim 20,wherein R22, R24, R26, and R28 each independently comprise belimumab, Mogamulizumab, Blinatumomab, Ibritumomab tiuxetan, Obinutuzumab, Ofatumumab, Rituximab, Inotuzumab ozogamicin, Moxetumomab pasudotox, Brentuximab vedotin, Daratumumab, Ipilimumab, Cetuximab, Necitumumab, Panitumumab, Dinutuximab, Pertuzumab, Trastuzumab, Trastuzumab emtansine, Siltuximab, Cemiplimab, Nivolumab, Pembrolizumab, Olaratumab, Atezolizumab, Avelumab, Durvalumab, Capromab pendetide, Elotuzumab, Denosumab, Ziv-aflibercept, Bevacizumab, Ramucirumab, Tositumomab, Gemtuzumab2026249088  09 Oct 2026ozogamicin, Alemtuzumab, Cixutumumab, Girentuximab, Nimotuzumab, Catumaxomab, Etaracizumab, an antigen-binding fragment of any thereof, a prostate specific membrane antigen (“PSMA”) binding peptide, a somatostatin receptor agonist, a bombesin receptor agonist, a seprase binding compound, or a binding fragement of any thereof.

22. The targeting compound of any one of claims 19-21, wherein the targeting compound of Formula II is of Formula Vor a pharmaceutically acceptable salt thereof, wherein M2 is an alpha-emitting radionuclide.

23. The targeting compound of claim 22, wherein M2 is actinium-225 (225Ac3+), radium-223 (233Ra2+), bismuth-213 (213Bi3+), lead-212 (212Pb2+ and / or 212Pb4+), terbium-149 (149Tb3+), fermium-255 (255Fm3+), thorium-227 (227Th4+), thorium-226 (226Th4+), astatine-211 (211At+), astatine-217 (217At+), or uranium-230.

24. The targeting compound of any one of claims 19-21, wherein the targeting compound of Formula II is of Formula VIIIor a pharmaceutically acceptable salt thereof, wherein M3 is an alpha-emitting radionuclide.

25. The targeting compound of claim 24, wherein M3 is actinium-225 (225Ac3+), radium-223 (233Ra2+), bismuth-213 (213Bi3+), lead-212 (212Pb2+ and / or 212Pb4+), terbium-149 (149Tb3+),2026249088  09 Oct 202626.fermium-255 (255Fm3+), thorium-227 (227Th4+), thorium-226 (226Th4+), astatine-211 (211At+), astatine-217 (217At+), or uranium-230.The targeting compound of any one of claims 19-21, wherein the targeting compound ofFormula II is of Formula XIR26(XI)or a pharmaceutically acceptable salt thereof, wherein M4 an alpha-emitting radionuclide.

27. The targeting compound of claim 26, wherein M4 is actinium-225 (225Ac3+), radium-223 (233Ra2+), bismuth-213 (213Bi3+), lead-212 (212Pb2+ and / or 212Pb4+), terbium-149 (149Tb3+), fermium-255 (255Fm3+), thorium-227 (227Th4+), thorium-226 (226Th4+), astatine-211 (211At+), astatine-217 (217At+), or uranium-230.

28. The targeting compound of any one of claims 19-21, wherein the targeting compound ofFormula II is of Formula XIV(XIV)or a pharmaceutically acceptable salt thereof, wherein M5 is an alpha-emittingradionuclide.

29. The targeting compound of claim 28, wherein M5 is actinium-225 (225Ac3+), radium-223 (233Ra2+), bismuth-213 (213Bi3+), lead-212 (212Pb2+ and / or 212Pb4+), terbium-149 (149Tb3+), fermium-255 (255Fm3+), thorium-227 (227Th4+), thorium-226 (226Th4+), astatine-211 (211At+), astatine-217 (217At+), or uranium-230.2026249088  09 Oct 202630. A modified antibody, modified antibody fragment, or modified binding peptide comprising a linkage arising from conjugation of a compound of Formula IZ1 is H or -X1-W2Z2 is OH or NH-W3Z3 is H or W7; a is 0 or 1;X1 is O, NH, or S;W2 and W3 are each independently H, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl, heteroaryl, -CH2CH2-(OCH2CH2)w-R’ where w is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, or -CH2CH2-(OCH2CH2)x-OR’ where x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, each of which may optionally be substituted with one or more of halo, -N3, -OR’, -CH2CH2-(OCH2CH2)y-R’ where y is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, -CH2CH2-(OCH2CH2)z-OR’ where z is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, -SR’, -OC(O)R’, -C(O)OR’, -C(S)OR’, -S(O)R’, -SO2R’, -SO2(OR’), -SO2NR’2, -P(O)(OR’)2, -P(O)R’(OR’), -P(O)R’2, -CN, -OCN, -SCN, -NCO, -NCS, -NR’-NH2, -N=C=N-R’, -SO2Cl, -C(O)Cl, or an epoxide group;W5 and W7 are each independently OH, NH2, SH, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl, heteroaryl, -CH2CH2-(OCH2CH2)w-R’ where w is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, or -CH2CH2-(OCH2CH2)x-OR’ where x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, each of which may optionally be substituted with one or more of halo, -N3, -OR’, -CH2CH2-(OCH2CH2)yx-R’ where y is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, -CH2CH2-(OCH2CH2)z-OR’ where z is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, -SR’, -OC(O)R’, -C(O)OR’, -C(S)OR’, -S(O)R’, -SO2R’, -SO2(OR’), -SO2NR’2, -P(O)(OR’)2, -P(O)R’(OR’), -P(O)R’2, -CN, -OCN, -SCN, -NCO, -NCS, -NR’-NH2, -N=C=N-R’, -SO2Cl, -C(O)Cl, or an epoxide group; and2026249088  09 Oct 2026R’ is independently at each occurance H, halo, -N3, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C5-C8 cycloalkenyl, C2-C6 alkynyl, C8-C10 cycloalkynyl, C5-C6 aryl, heterocyclyl, or heteroaryl.

31. The modified antibody, modified antibody fragment, or modified binding peptide of claim 30, wherein the antibody comprises belimumab, Mogamulizumab, Blinatumomab, Ibritumomab tiuxetan, Obinutuzumab, Ofatumumab, Rituximab, Inotuzumab ozogamicin, Moxetumomab pasudotox, Brentuximab vedotin, Daratumumab, Ipilimumab, Cetuximab, Necitumumab, Panitumumab, Dinutuximab, Pertuzumab, Trastuzumab, Trastuzumab emtansine, Siltuximab, Cemiplimab, Nivolumab, Pembrolizumab, Olaratumab, Atezolizumab, Avelumab, Durvalumab, Capromab pendetide, Elotuzumab, Denosumab, Ziv-aflibercept, Bevacizumab, Ramucirumab, Tositumomab, Gemtuzumab ozogamicin, Alemtuzumab, Cixutumumab, Girentuximab, Nimotuzumab, Catumaxomab, or Etaracizumab.

32. The modified antibody, modified antibody fragment, or modified binding peptide of claim 30 or claim 31, wherein the antibody fragment comprises an antigen-binding fragment of belimumab, Mogamulizumab, Blinatumomab, Ibritumomab tiuxetan, Obinutuzumab, Ofatumumab, Rituximab, Inotuzumab ozogamicin, Moxetumomab pasudotox, Brentuximab vedotin, Daratumumab, Ipilimumab, Cetuximab, Necitumumab, Panitumumab, Dinutuximab, Pertuzumab, Trastuzumab, Trastuzumab emtansine, Siltuximab, Cemiplimab, Nivolumab, Pembrolizumab, Olaratumab, Atezolizumab, Avelumab, Durvalumab, Capromab pendetide, Elotuzumab, Denosumab, Ziv-aflibercept, Bevacizumab, Ramucirumab, Tositumomab, Gemtuzumab ozogamicin, Alemtuzumab, Cixutumumab, Girentuximab, Nimotuzumab, Catumaxomab, or Etaracizumab.

33. The modified antibody, modified antibody fragment, or modified binding peptide of any one of claims 30-32, wherein the binding peptide comprises comprises a prostate specific membrane antigen (“PSMA”) binding peptide, a somatostatin receptor agonist, a bombesin receptor agonist, a seprase binding compound, or a binding fragement thereof.

34. The modified antibody, modified antibody fragment, or modified binding peptideof any one of claims 30-33, wherein the compound of Formula I is of Formula III2026249088  09 Oct 2026or a pharmaceutically acceptable salt thereof.

35. The modified antibody, modified antibody fragment, or modified binding peptideof any one of claims 30-34, wherein the linkage is a thiocyante linkage; wherein the thiocyanate linkage arises from conjugation of the compound with the antibody, antibody fragment, or binding peptide; and wherein the compound is SCNor pharmaceutically acceptable salt thereof.

36. The modified antibody, modified antibody fragment, or modified binding peptideof any one of claims 30-33, wherein the compound of Formula I is of Formula VIor a pharmaceutically acceptable salt thereof.

37. The modified antibody, modified antibody fragment, or modified binding peptideof any one of claims 30-33, wherein the compound of Formula I is of Formula IX2026249088  09 Oct 2026or a pharmaceutically acceptable salt thereof.

38. The modified antibody, modified antibody fragment, or modified binding peptideof any one of claims 30-33, wherein the compound of Formula I is of Formula XII(XII)or a pharmaceutically acceptable salt thereof.

39. A modified antibody, modified antibody fragment, or modified binding peptide comprising a linkage arising from conjugation of a compound of Formula IA(IA) or a pharmaceutically acceptable salt thereof,with an antibody, antibody fragment, or binding peptide, whereinM1 is an alpha-emitting radionuclide;Z1 is H or -X1-W2Z2 is OH or NH-W3Z3 is H or W7;a is 0 or 1;X1 is O, NH, or S;2026249088  09 Oct 2026W2 and W3 are each independently H, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl, heteroaryl, -CH2CH2-(OCH2CH2)w-R’ where w is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, or -CH2CH2-(OCH2CH2)x-OR’ where x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, each of which may optionally be substituted with one or more of halo, -N3, -OR’, -CH2CH2-(OCH2CH2)y-R’ where y is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, -CH2CH2-(OCH2CH2)z-OR’ where z is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, -SR’, -OC(O)R’, -C(O)OR’, -C(S)OR’, -S(O)R’, -SO2R’, -SO2(OR’), -SO2NR’2, -P(O)(OR’)2, -P(O)R’(OR’), -P(O)R’2, -CN, -OCN, -SCN, -NCO, -NCS, -NR’-NH2, -N=C=N-R’, -SO2Cl, -C(O)Cl, or an epoxide group;W5 and W7 are each independently OH, NH2, SH, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl, heteroaryl, -CH2CH2-(OCH2CH2)w-R’ where w is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, or -CH2CH2-(OCH2CH2)x-OR’ where x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, each of which may optionally be substituted with one or more of halo, -N3, -OR’, -CH2CH2-(OCH2CH2)yx-R’ where y is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, -CH2CH2-(OCH2CH2)z-OR’ where z is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, -SR’, -OC(O)R’, -C(O)OR’, -C(S)OR’, -S(O)R’, -SO2R’, -SO2(OR’), -SO2NR’2, -P(O)(OR’)2, -P(O)R’(OR’), -P(O)R’2, -CN, -OCN, -SCN, -NCO, -NCS, -NR’-NH2, -N=C=N-R’, -SO2Cl, -C(O)Cl, or an epoxide group; andR’ is independently at each occurance H, halo, -N3, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C5-C8 cycloalkenyl, C2-C6 alkynyl, C8-C10 cycloalkynyl, C5-C6 aryl, heterocyclyl, or heteroaryl.

40. The modified antibody, modified antibody fragment, or modified binding peptide of claim 39, wherein M1 is actinium-225 (225Ac3+), radium-223 (233Ra2+), bismuth-213 (213Bi3+), lead-212 (212Pb2+ and / or 212Pb4+), terbium-149 (149Tb3+), fermium-255 (255Fm3+), thorium-227 (227Th4+), thorium-226 (226Th4+), astatine-211 (211At+), astatine-217 (217At+), or uranium-230.

41. The modified antibody, modified antibody fragment, or modified binding peptide of claim 39 or claim 40, wherein the antibody comprises belimumab, Mogamulizumab, Blinatumomab, Ibritumomab tiuxetan, Obinutuzumab, Ofatumumab, Rituximab, Inotuzumab ozogamicin, Moxetumomab pasudotox, Brentuximab vedotin, Daratumumab, Ipilimumab, Cetuximab, Necitumumab, Panitumumab, Dinutuximab,2026249088  09 Oct 2026Pertuzumab, Trastuzumab, Trastuzumab emtansine, Siltuximab, Cemiplimab, Nivolumab, Pembrolizumab, Olaratumab, Atezolizumab, Avelumab, Durvalumab, Capromab pendetide, Elotuzumab, Denosumab, Ziv-aflibercept, Bevacizumab, Ramucirumab, Tositumomab, Gemtuzumab ozogamicin, Alemtuzumab, Cixutumumab, Girentuximab, Nimotuzumab, Catumaxomab, or Etaracizumab.

42. The modified antibody, modified antibody fragment, or modified binding peptide of any one of claims 39-41, wherein the antibody fragment comprises an antigen-binding fragment of belimumab, Mogamulizumab, Blinatumomab, Ibritumomab tiuxetan, Obinutuzumab, Ofatumumab, Rituximab, Inotuzumab ozogamicin, Moxetumomab pasudotox, Brentuximab vedotin, Daratumumab, Ipilimumab, Cetuximab, Necitumumab, Panitumumab, Dinutuximab, Pertuzumab, Trastuzumab, Trastuzumab emtansine, Siltuximab, Cemiplimab, Nivolumab, Pembrolizumab, Olaratumab, Atezolizumab, Avelumab, Durvalumab, Capromab pendetide, Elotuzumab, Denosumab, Ziv-aflibercept, Bevacizumab, Ramucirumab, Tositumomab, Gemtuzumab ozogamicin, Alemtuzumab, Cixutumumab, Girentuximab, Nimotuzumab, Catumaxomab, or Etaracizumab.

43. The modified antibody, modified antibody fragment, or modified binding peptide of any one of claims 39-42, wherein the binding peptide comprises a prostate specific membrane antigen (“PSMA”) binding peptide, a somatostatin receptor agonist, a bombesin receptor agonist, a seprase binding compound, or a binding fragement thereof.

44. The modified antibody, modified antibody fragment, or modified binding peptide of any one of claims 39-43, wherein the compound of Formula I is of Formula IV(IV)or a pharmaceutically acceptable salt thereof, wherein M2 is an alpha-emitting radionuclide.

45. The modified antibody, modified antibody fragment, or modified binding peptide of claim 44, wherein M2 is actinium-225 (225Ac3+), radium-223 (233Ra2+), bismuth-213 (213Bi3+), lead-212 (212Pb2+ and / or 212Pb4+), terbium-149 (149Tb3+), fermium-255 (255Fm3+),2026249088  09 Oct 2026thorium-227 (227Th4+), thorium-226 (226Th4+), astatine-211 (211At+), astatine-217 (217At+), or uranium-230.

46. The modified antibody, modified antibody fragment, or modified binding peptide of claim 44, wherein the linkage is a thiocyante linkage; wherein the thiocyanate linkage arises from conjugation of the compound with the antibody, antibody fragment, or binding peptide; and wherein the compound is47. The modified antibody, modified antibody fragment, or modified binding peptide of claim 46, wherein M2 is actinium-225 (225Ac3+), radium-223 (233Ra2+), bismuth-213 (213Bi3+), lead-212 (212Pb2+ and / or 212Pb4+), terbium-149 (149Tb3+), fermium-255 (255Fm3+), thorium-227 (227Th4+), thorium-226 (226Th4+), astatine-211 (211At+), astatine-217 (217At+), or uranium-230.

48. The modified antibody, modified antibody fragment, or modified binding peptide of any one of claims 39-43, wherein the compound of Formula IA is of Formula VIIIrCh(_ N O-7 (Z\= /    \— /    \= / 0H>nhO \ 3W3                     (VII)or a pharmaceutically acceptable salt thereof, wherein M3 is an alpha-emitting radionuclide.

49. The modified antibody, modified antibody fragment, or modified binding peptide of claim48, wherein M3 is actinium-225 (225Ac3+), radium-223 (233Ra2+), bismuth-213 (213Bi3+), lead-212 (212Pb2+ and / or 212Pb4+), terbium-149 (149Tb3+), fermium-255 (255Fm3+),2026249088  09 Oct 2026thorium-227 (227Th4+), thorium-226 (226Th4+), astatine-211 (211At+), astatine-217 (217At+), or uranium-230.

50. The modified antibody, modified antibody fragment, or modified binding peptide of any one of claims 39-43, wherein the compound of Formula IA is of Formula Xor a pharmaceutically acceptable salt thereof, wherein M4 is an alpha-emitting radionuclide.

51. The modified antibody, modified antibody fragment, or modified binding peptide of claim 50, wherein M4 is actinium-225 (225Ac3+), radium-223 (233Ra2+), bismuth-213 (213Bi3+), lead-212 (212Pb2+ and / or 212Pb4+), terbium-149 (149Tb3+), fermium-255 (255Fm3+), thorium-227 (227Th4+), thorium-226 (226Th4+), astatine-211 (211At+), astatine-217 (217At+), or uranium-230.

52. The modified antibody, modified antibody fragment, or modified binding peptide of any one of claims 39-43, wherein the compound of Formula IA is of Formula XIII(XIII)or a pharmaceutically acceptable salt thereof, wherein M5 is an alpha-emitting radionuclide.

53. The modified antibody, modified antibody fragment, or modified binding peptide of claim 52, wherein M5 is actinium-225 (225Ac3+), radium-223 (233Ra2+), bismuth-213 (213Bi3+), lead-212 (212Pb2+ and / or 212Pb4+), terbium-149 (149Tb3+), fermium-255 (255Fm3+), thorium-227 (227Th4+), thorium-226 (226Th4+), astatine-211 (211At+), astatine-217 (217At+), or uranium-230.2026249088  09 Oct 202654. A composition comprising a pharmaceutically acceptable carrier and a compound of any one of claims 1-18.

55. A composition comprising a pharmaceutically acceptable carrier and a targeting compound of any one of claims 19-29 or comprising a pharmaceutically acceptable carrier and a modified antibody, modified antibody fragment, or modified binding peptide of any one of claims 30-53.

56. A pharmaceutical composition useful in targeted radiotherapy of cancer and / or mammalian tissue overexpressing prostate specific membrane antigen (“PSMA”) in a subject, wherein the pharmaceutical composition comprises a pharmaceutically acceptable carrier and a compound of any one of claims 19-29 or a modified antibody, modified antibody fragment, or modified binding peptide of any one of claims 30-53.

57. The pharmaceutical composition of claim 56, wherein the pharmaceutical composition comprises an effective amount for treating the cancer and / or mammalian tissue overexpressing PSMA of the compound or an effective amount for treating the cancer and / or mammalian tissue overexpressing PSMA of the modified antibody, modified antibody fragment, or modified binding peptide.

58. The pharmaceutical composition of claim 56 or claim 57, where the subject suffers from a mammalian tissue expressing a somatostatin receptor, a bombesin receptor, seprase, or a combination of any two or more thereof, and / or mammalian tissue overexpressing PSMA.

59. The pharmaceutical composition of any one of claims 56-58, wherein the subject suffers from one or more of a growth hormone producing tumor, a neuroendocrine tumor, a pituitary tumor, a vasoactive intestinal peptide-secreting tumor, a small cell carcinoma of the lung, gastric cancer tissue, pancreatic cancer tissue, a neuroblastoma,60. The pharmaceutical composition of any one of claims 56-59, wherein the subject suffers from one or more of a glioma, a breast cancer, an adrenal cortical cancer, a cervical carcinoma, a vulvar carcinoma, an endometrial carcinoma, a primary ovarian carcinoma, a metastatic ovarian carcinoma, a non-small cell lung cancer, a small cell lung cancer, a bladder cancer, a colon cancer, a primary gastric adenocarcinoma, a primary colorectal adenocarcinoma, a renal cell carcinoma, and a prostate cancer.2026249088  09 Oct 202661. The pharmaceutical composition of any one of claims 56-60, wherein the pharmaceutical composition is formulated for intraveneous administration, optionally comprising sterilized water, Ringer's solution, or an isotonic aqueous saline solution.

62. The pharmaceutical composition of any one of 57-61, wherein the effective amount of the compound is from about 0.01 pg to about 10 mg of the compound per gram of the pharmaceutical composition.

63. The pharmaceutical composition of any one of claims 56-62, wherein the pharmaceutical composition is provided in an injectable dosage form.

64. A method of treating a subject, wherein the method comprises administering a targeting compound of any one of claims 19-29 to the subject or administering a modified antibody, modified antibody fragment, or modified binding peptide of any one of claims 30-53.

65. The method of claim 64, wherein the subject suffers from cancer and / or mammalian tissue overexpressing prostate specific membrane antigen (“PSMA”)66. The method of claim 65, wherein the method comprises administering an effective amount for treating the cancer and / or mammalian tissue overexpressing PSMA of the compound or an effective amount for treating the cancer and / or mammalian tissue overexpressing PSMA of the modified antibody, modified antibody fragment, or modified binding peptide67. The method of any one of claims 64-66, wherein the subject suffers from a mammalian tissue expressing a somatostatin receptor, a bombesin receptor, seprase, or a combination of any two or more thereof and / or mammalian tissue overexpressing prostate specific membrane antigen (“PSMA”).

68. The method of any one of claims 64-67, wherein the mammalian tissue comprises one or more of a growth hormone producing tumor, a neuroendocrine tumor, a pituitary tumor, a vasoactive intestinal peptide-secreting tumor, a small cell carcinoma of the lung, gastric cancer tissue, pancreatic cancer tissue, a neuroblastoma, and a metastatic cancer.

69. The method of any one of claims 64-68, wherein the subject suffers from one or more of a glioma, a breast cancer, an adrenal cortical cancer, a cervical carcinoma, a vulvar carcinoma, an endometrial carcinoma, a primary ovarian carcinoma, a metastatic ovarian2026249088  09 Oct 2026carcinoma, a non-small cell lung cancer, a small cell lung cancer, a bladder cancer, a colon cancer, a primary gastric adenocarcinoma, a primary colorectal adenocarcinoma, a renal cell carcinoma, and a prostate cancer.

70. The method of any one of claims 64-69, wherein the administering comprises parenteral administration.

71. The method of any one of claims 64-70, wherein the administeringcomprises intraveneous administration.

72. The method of any one of claims 66-71, wherein the effective amount is from about 0.1 pg to about 50 pg per kilogram of subject mass.

73. A compound comprising a first domain having a blood-protein binding moiety with low specific affinity for the blood-protein, a second domain having a tumor targeting moiety with high affinity for a tumor antigen, and a third domain having a chelator.

74. The compound of claim 73, wherein the tumor antigen is PSMA, bombesin, somatostatin receptor, or seprase.

75. The compound of claim 73, wherein the blood protein binding moiety has specific affinity for albumin of about 0.5-50 x 10-6M, and the tumor targeting moiety has specific affinity for the tumor antigen of about 0.5-50 x 10-9M.2026249088 09 Oct 202676. A compound represented by the following structure r" / —N O )   VoH ■d ° HN >s HN               r ( HN— q >4 ANH O / -0 0-' O Al A A. JL HN N^V^N^ CO2H               Nn \u ho2c n n co2h H H or a pharmaceutically acceptable salt thereof.

77. A composition comprising the compound of claim 76 chelating 213Bi3+, 211At+,' 2^(-,2+ , or 212Pb4+. ~y                             HNA o-^                              ° N^              HN^ ) d-N O           aA CO2H o—7 d W        O-- o -7    ^=7 OH      / —7 0^ o^ ,25Ac3d 152Dy3+) 212Bi3+ 211Bi3+ 217^+, 227^4+ 226^4+ 233^2+178

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