Fibroblast Activation Protein (FAP) Inhibitors, FAP Conjugates, and Their Diagnostic and Therapeutic Uses - Patent application

Abstract

The present disclosure relates to the field of fibroblast activation protein (FAP) inhibitors, conjugates containing novel FAP inhibitors, including radiotracers, for imaging, diagnosis and treatment of conditions characterized by overexpression of FAP.

Description

[Technical Field]

[0001] 1. Background The present disclosure is directed to novel fibroblast activation protein (FAP) inhibitors, including radiotracers, and conjugates comprising the novel FAP inhibitors, for the diagnosis and treatment of conditions characterized by the expression of FAP. [Background technology]

[0002] In nuclear medicine, radiotracers are used in the diagnosis and treatment of various conditions and diseases. A radiotracer is a compound in which a radionuclide is linked to a targeting moiety that targets specific organs, cells, or biomarkers in the human body.

[0003] Radiotracers involve the use of targeting moieties that selectively localize to malignant cells, tumors, or their associated microenvironment, and the use of low-range, highly ionizing radiation, e.g., α or β - Radionuclides selected to emit particles and Auger electrons can be used in targeted radionuclide therapy. The combination of disease diagnosis and treatment, utilizing the same or similar biological targeting moieties to target specific biomarkers (e.g., cell surface receptors) with different diagnostic and therapeutic radionuclides, is called targeted theranostics. This approach overcomes the difficulty of quantifying the individual doses required for treatment through diagnosis, allowing for highly personalized patient treatment. The theranostics approach utilizes isotopically distinct radiotracers that bind identically to biomarkers, and thus utilizes radionuclides of the same element, such as copper radionuclides as positron emitters in diagnostic imaging. 60 Cu, 61 Cu, 62 Cu and 64 Cu and β in radiation therapy - As an emitter 67 Further improvement is achieved using Cu.

[0004] FAP is a transmembrane glycoprotein expressed on activated fibroblasts (e.g., cancer-associated fibroblasts (CAFs)) and is a major component of the tumor microenvironment. Structurally, FAP is a type II transmembrane glycoprotein consisting of 760 amino acids. FAP is a serine protease and, unlike other members of the dipeptidyl peptidase (DPP) family, possesses both endopeptidase and exopeptidase activities, which enable FAP to cleave gelatin and type I collagen, thereby playing an important role in extracellular matrix (ECM) remodeling. FAP-expressing CAFs are found in various neoplasms, particularly epithelial cancers, and in malignant tumors with strong desmoplastic responses, such as breast, colorectal, pancreatic, and lung cancers. Overall, high FAP expression is associated with tumor aggressiveness and poor prognosis (Cohen, SJ; Alpaugh, RK; Palazzo, I.; Meropol, NJ; Rogatko, A.; Xu, Z.; Hoffman, JP; Weiner, LM; Cheng, JD "Fibroblast Activation Protein and Its Relationship to Clinical Outcome in Pancreatic Adenocarcinoma." Pancreas 2008, 37, 154-158). The minimal expression of FAP in normal healthy adult tissues makes it an attractive target for oncological imaging and therapy (Lindner, T.; Loktev, A.; Giesel, F.; Kratochwil, C.; Altmann, A.; Haberkorn, U "Targeting of Activated Fibroblasts for Imaging and Therapy." "Fibroblasts for Imaging and Therapy)" EJNMMI Radiopharm.Chem.2019,4,16.).

[0005] FAP overexpression was targeted by small molecule FAP inhibitors (also known as "FAPIs") with an N-(4-quinolinoyl)-Gly-(2-cyanopyrrolidine) scaffold, initially developed at the University of Antwerp (Hansen, K.; Heirbaut, L.; Cheng, J.D.; Joossens, J.; Ryabtsova, O.; Cos, P.; Maes, L.; Lambeir, A.-M.; De Meester, I.; Augustyns, K.; et al. "Selective Inhibitors of Fibroblast Activation Protein (FAP) with a (4-Quinolinoyl)-Glycyl-2-Cyanopyrrolidine Scaffold," ACS). Med. Chem. Lett. 2013, 4, 491-496; Jansen, K.; Heirbaut, L.; Verkerk, R.; Cheng, JD; Joossens, J.; Cos, P.; Maes, L.; Lambeir, A.-M.; De Meester, I.; Augustyns, K.; et al. "Extended Structure-Activity Relationship and Pharmacokinetic Investigation of (4-Quinolinoyl)Glycyl-2-Cyanopyrrolidine Inhibitors of Fibroblast Activation Protein (FAP)" J. Med. Chem. 2014, 57, 3053-3074. By modifying this structure, we developed FAPI-01 and FAPI-02 as the first quinoline-based FAPIs, respectively. 125 I and 68 Ga / 177Further attempts to improve tumor retention led to the development of FAPI-46 (Loktev, A.; Lindner, T.; Burger, E.-M.; Altmann, A.; Giesel, F.; Kratochwil, C.; Debus, J.; Marme, F.; Jager, D.; Mier, W.; et al., "Development of Fibroblast Activation Protein-Targeted Radiotracers with Improved Tumor Retention," J. Nucl. Med. 2019, 60, 1421-1429). International Publication No. WO 2019 / 154886 describes FAP inhibitors, FAP inhibitor-chelator constructs, and radiolabeled FAP inhibitor-chelator constructs that are useful for diagnosing or treating diseases characterized by FAP overexpression (e.g., cancer).

[0006] Because FAP overexpression is not limited to CAFs, the use of FAP inhibitors in combination with positron emission tomography-computed tomography (PET-CT) may find application in a wide range of non-oncological pathological conditions, such as inflammatory, infectious, and immune disorders. FAP overexpression has also been associated with cardiovascular disease, liver fibrosis and cirrhosis, joint disorders (e.g., rheumatoid arthritis), IgG4-related disease, pulmonary fibrosis and interstitial lung disease, Crohn's disease, tuberculosis, sarcoidosis, and periprosthetic joint infections (Chandekar, KR; Prashanth, A.; Vinjamuri, S.; Kumar, R. FAP, "PET / CT Imaging—An Updated Review," Diagnostics 2023, 13, 2018).

[0007] The availability of a large portfolio of FAP inhibitors and radiotracers is essential for the development of nuclear medicine.

[0008] Accordingly, it is an object of the present disclosure to provide compounds, compositions and methods that completely or partially overcome one or more of the problems identified in the prior art involving FAP inhibitors; conjugates comprising FAP inhibitors (including pharmaceuticals and radiotracers); and uses thereof. Summary of the Invention

[0009] The present disclosure relates to improved FAP inhibitors, conjugates comprising the improved FAP inhibitors, and their use in the diagnosis and treatment of various diseases characterized by overexpression of FAPs.

[0010] In one aspect, provided herein is a compound, wherein the compound is a compound of Formula I: [ka] R 1 is R a and; R 2 and R 3 are R a or together with the nitrogen atom to which they are attached and C 2-9 Forming a heterocyclic ring; R 4 is H, an amine protecting group, or -LT; R a independently for each occurrence, H, C 1-10 Alkyl, C 2-10 Alkenyl, C 3-10 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, C 2-9 Heterocyclyl, or C 5-9heteroaryl, optionally substituted with one or more substituents selected from —OH, —OR′, ═O, ═S, —SH, —SR′, —NH, —NHR′, —N(R′) , —NHCOR′, —NR′COR′, halogen, —CN, —COH, —COR′, —CHO, —COR′, —CONH, —CONHR′, —CON(R′) , —NO , —OP(O)(OH) , —SOH, —SOR′, —SOR′, and —SOR′; R′ is independently for each occurrence C 1-10 Alkyl or C 3-10 is cycloalkyl; L is a bond or a bivalent linker; T comprises (a) a chelating moiety suitable for chelating a radionuclide, (b) an imaging agent, or (c) a drug; n is an integer from 1 to 20; m is an integer from 1 to 20; or a pharmaceutically acceptable salt thereof.

[0011] In another embodiment, the compound is a compound of formula II: [ka] R 3 is H, C 1-10 Alkyl, C 2-10 Alkenyl, C 3-10 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, C 2-9 Heterocyclyl, or C 5-9 heteroaryl, optionally substituted with one or more substituents selected from —OH, —OR′, ═O, ═S, —SH, —SR′, —NH, —NHR′, —N(R′) , —NHCOR′, —NR′COR′, halogen, —CN, —COH, —COR′, —CHO, —COR′, —CONH, —CONHR′, —CON(R′) , —NO , —OP(O)(OH) , —SOH, —SOR′, —SOR′, and —SOR′; R′ is independently for each occurrence C 1-10 Alkyl or C 3-10is cycloalkyl; or R 3 together with the L moiety, form a bond between the nitrogen atom and C 2-9 Forming a heterocyclic ring; L is a bivalent linker, preferably up to 20 atoms in length; or a pharmaceutically acceptable salt thereof.

[0012] In another embodiment, the compound is a compound of formula III: [ka] R 3 is H, C 1-10 Alkyl, C 2-10 Alkenyl, C 3-10 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, C 2-9 Heterocyclyl, or C 5-9 heteroaryl, optionally substituted with one or more substituents selected from —OH, —OR′, ═O, ═S, —SH, —SR′, —NH, —NHR′, —N(R′) , —NHCOR′, —NR′COR′, halogen, —CN, —COH, —COR′, —CHO, —COR′, —CONH, —CONHR′, —CON(R′) , —NO , —OP(O)(OH) , —SOH, —SOR′, —SOR′, and —SOR′; R′ is independently for each occurrence C 1-10 Alkyl or C 3-10 is cycloalkyl; or R 3 together with the L moiety, form a bond between the nitrogen atom and C 2-9 Forming a heterocyclic ring; L is a bivalent linker, preferably up to 20 atoms in length; M is 225 Ac, 51 Cr, 66 Ga, 67 Ga, 68 Ga, [ 18 F]AlF, 111 In, 113m In,52m Mn、 99m Tc、 186 Re, 188 Re, 139 At, 140 At, 175 Yb、 179 Yb、 153 Sm、 177m Sn、 166 Hey, 86 Y、 88 Y、 90 Y、 149 P.m, 165 Dy, 169 Err, 177 Monday 52 Fe、 43 Sc、 44 Sc、 46 Sc、 47 Sc、 142 Mr. 157 Gd、 159 Gd、 212 Yes, 213 Yes, 72 Ace, 77 Ace, 97 Ru、 109 Pd, 105 Rh, 101m Rh, 119 Saturday, 197 Hg、 151 I, 153 I, 169 I, 201 Tl, 149 Tb、 152 Tb、 155 Tb、 161 Tb、 203 Pb、 212 Pb、 151 P.m, 153 P.m, 142 Mr. 143 Mr. 55 Who, 60 With, 61 With, 62 With, 64 With, 67 With, 62 Yes, 188 Re, 198 Have, 199 Have, 227 Th、 111 Ag、 199Ag, 211 At, 223 Ra, 88 Zr and 89 Selected from Zr; or a pharmaceutically acceptable salt thereof.

[0013] In another aspect, compositions, including pharmaceutical compositions and radiotracer compositions, comprising the compounds described herein are provided.

[0014] In another aspect, a method of generating one or more images of a subject is provided, the method comprising administering to the subject an effective amount of a compound described herein comprising a radionuclide or a pharmaceutical composition comprising the same, and generating one or more images of at least a portion of the subject's body using, for example, positron emission tomography (PET), PET-computed tomography (PET-CT), or single photon emission computed tomography (SPECT).

[0015] In another aspect of the present disclosure, there is provided a method of detecting a disease in a subject, the method comprising administering to the subject a compound described herein comprising a radionuclide or a pharmaceutical composition comprising the same, detecting localization of the radionuclide in the subject, for example using PET, PET-CT or SPECT, and determining the presence or absence of the disease based on the presence or absence of localization.

[0016] In another aspect of the present disclosure, there is provided a method for monitoring the effectiveness of cancer treatment in a subject suffering from cancer, the method comprising administering to the subject an effective amount of a compound described herein comprising a radionuclide or a pharmaceutical composition comprising the same, detecting localization of the radionuclide in the subject, for example using PET, PET-CT or SPECT, and determining the effectiveness of the cancer treatment.

[0017] In another aspect of the disclosure, there is provided a method of treating a disease in a patient suffering from the disease, the treatment comprising administering to the patient an effective amount of a compound or pharmaceutical composition described herein.

[0018] In another aspect of the present disclosure, a theranostic method is provided, the method comprising: (a) administering to a subject a therapeutic agent as described herein; 61 (b) administering to a subject an effective amount of a first compound comprising a Cu radionuclide or a pharmaceutical composition comprising the same; and (c) generating one or more images of the subject (e.g., of a particular region or portion of the subject's body). 67 administering to the subject an effective amount of a compound containing a Cu radionuclide or a pharmaceutical composition containing the same, wherein the compounds of steps (a) and (c) differ only in the identity of the radioisotope.

[0019] 3. Brief description of the drawings These and other features, aspects, and advantages of the present disclosure will become better understood with regard to the following description and accompanying drawings. [Brief explanation of the drawings]

[0020] [Figure 1] Partition coefficients (logD PBS / octanol, pH=7.4) of Cu- or Ga-labeled conjugates. From left to right: [Cu]Cu-NODAGA-1, [Cu]Cu-NODAGA-3, [Cu]Cu-NODAGA-2, [Cu]Cu-NODAGA-4, [Ga]Ga-FAPI-46, and [Cu]Cu-NODAGA-FAPI-46.

[0021] [Figure 2] FIG. 1 shows the inhibition (IC50) of natCu-labeled conjugates.

[0022] [Figure 3]Panel A shows the cell surface cellular uptake (membrane-bound) and internalized fraction of [61Cu]Cu-NODAGA-1, panel B shows the cell surface cellular uptake (membrane-bound) and internalized fraction of [61Cu]Cu-NODAGA-3, panel C shows the cell surface cellular uptake (membrane-bound) and internalized fraction of [61Cu]Cu-NODAGA-2, and panel D shows the cell surface cellular uptake (membrane-bound) and internalized fraction of [61Cu]Cu-NODAGA-4. Values ​​are expressed as % of irradiated radioactivity and refer to specific uptake calculated after subtracting the nonspecific value (measured in the presence of the non-FAP-expressing cell line HT-1080.wt) from the total value (specific = total - nonspecific).

[0023] [Figure 4] Figure 1 shows the cell surface uptake (cell membrane-bound) and internalized fraction of [Cu]Cu-NODAGA-FAPI-46. Values ​​are expressed as % of delivered radioactivity and refer to specific uptake calculated after subtracting the nonspecific value (measured in the presence of the non-FAP-expressing cell line HT-1080.wt) from the total value (specific = total - nonspecific).

[0024] [Figure 5] FIG. 1 shows saturable binding of 61Cu-labeled conjugates in isolated HEK-293-hFAP membranes.

[0025] [Figure 6] Panel A shows the biodistribution profile of [61Cu]Cu-NODAGA-FAPI-46 in HT-1080.hFAP tumor-bearing mice 1 and 4 hours after administration, and panel B shows the biodistribution profile of [68Ga]Ga-FAPI-46 in HT-1080.hFAP tumor-bearing mice 1 and 4 hours after administration.

[0026] [Figure 7]Panel A shows the tumor-to-organ ratios of [61Cu]Cu-NODAGA-FAPI-46 in HT-1080.hFAP tumor-bearing mice 1 and 3 hours after administration, and panel B shows the tumor-to-organ ratios of [68Ga]Ga-FAPI-46 in HT-1080.hFAP tumor-bearing mice 1 and 3 hours after administration.

[0027] [Figure 8] Panel A shows the biodistribution profile of [61Cu]Cu-NODAGA-1 in HT-1080.hFAP tumor-bearing mice 1 and 4 hours after administration, and panel B shows the biodistribution profile of [61Cu]Cu-NODAGA-3 in HT-1080.hFAP tumor-bearing mice 1 and 4 hours after administration.

[0028] [Figure 9] Panel A shows the biodistribution profile of [61Cu]Cu-NODAGA-2 in HT-1080.hFAP tumor-bearing mice 1 hour and 3 hours after administration, and panel B shows the biodistribution profile of [61Cu]Cu-NODAGA-4 in HT-1080.hFAP tumor-bearing mice 1 hour and 3 hours after administration.

[0029] [Figure 10] Panel A shows the tumor-to-organ ratios of [61Cu]Cu-NODAGA-1 in HT-1080.hFAP tumor-bearing mice 1 and 4 hours after administration, and panel B shows the tumor-to-organ ratios of [61Cu]Cu-NODAGA-3 in HT-1080.hFAP tumor-bearing mice 1 and 4 hours after administration.

[0030] [Figure 11] Panel A shows the tumor-to-organ ratios of [61Cu]Cu-NODAGA-2 in HT-1080.hFAP tumor-bearing mice 1 and 4 hours after administration, and panel B shows the tumor-to-organ ratios of [61Cu]Cu-NODAGA-4 in HT-1080.hFAP tumor-bearing mice 1 and 4 hours after administration.

[0031] [Figure 12] 1 shows dynamic PET / CT scans of [61Cu]Cu-NODAGA-1 and [61Cu]Cu-NODAGA-3 in mice bearing FAP-positive xenografts.

[0032] [Figure 13] Panel A shows a dynamic PET / CT scan of [61Cu]Cu-NODAGA-2 in a mouse bearing a FAP-positive xenograft, and panel B shows a dynamic PET / CT scan of [61Cu]Cu-NODAGA-4 in a mouse bearing a FAP-positive xenograft.

[0033] [Figure 14] Panel A shows a dynamic PET / CT scan of [61Cu]Cu-NODAGA-FAPI-46 in a mouse bearing a FAP-positive xenograft, and panel B shows a dynamic PET / CT scan of [68Ga]Ga-FAPI-46 in a mouse bearing a FAP-positive xenograft.

[0034] [Figure 15] Panel A shows SUV PET imaging of [61Cu]Cu-NODAGA-2 and [61Cu]Cu-NODAGA-4 (1 hour and 4 hours), and panel B shows SUV PET imaging of [61Cu]Cu-NODAGA-FAPI-46 versus 68Ga-FAPI-46 ([61Cu]Cu-NODAGA-FAPI-46 at 1 hour and 4 hours, 68Ga-FAPI-46 at 1 hour only).

[0035] [Figure 16] Panels A-C show at increasing magnifications a uniform Ni coating with durable adhesion to the niobium coin upon completion of electroplating, as assessed using a DINOLite digital microscope to observe the crystal structure and surface uniformity.

[0036] [Figure 17]Shown is a sample of a target backing coin with nickel electrodeposited in the center of a niobium backing.

[0037] [Figure 18] Analysis of the 61Cu purity of a [61Cu]CuCl2 solution obtained by irradiation of natNi on a Nb backing with an 8.4 MeV deuteron beam at 50 μA for 3 hours. The line graph corresponds to the evolution of the 61Cu purity % over time, and the bar graph corresponds to the radioactive cobalt activity over time.

[0038] [Figure 19] Analysis of the 61Cu purity of a [61Cu]CuCl2 solution obtained by irradiation of 60Ni on a Nb backing with an 8.4 MeV deuteron beam at 50 μA for 3 hours. The line graph corresponds to the evolution of the 61Cu purity % over time, and the bar graph corresponds to the radioactive cobalt activity over time.

[0039] [Figure 20] 1 compares the radionuclide purity of a [61Cu]CuCl2 solution produced using a commercially available natNi target on an Ag backing with the radionuclide purity of a [61Cu]CuCl2 solution produced according to certain embodiments of the present disclosure, as assessed by gamma spectroscopy in Bq / g. Ag and Co isotopes are significantly reduced in the [61Cu]CuCl2 solution (indicating specific radionuclide impurities) when produced by irradiation of a Ni target electroplated according to the present disclosure on a high-purity Nb backing.

[0040] [Figure 21]Figure 1 shows a comparison of the radionuclide purity, as assessed by gamma spectroscopy (Bq / g, total radionuclide impurities), of a [61Cu]CuCl solution produced using a commercially available natNi target (Ag backing) with that of a [61Cu]CuCl solution produced by irradiation of a Ni target electroplated in accordance with the present disclosure onto a high-purity Nb backing. The presented data particularly highlights the reduction in overall impurities in the [61Cu]CuCl solution when produced by embodiments of the present disclosure.

[0041] [Figure 22] Figure 1 shows a comparison of the radionuclide purity (Bq / g, total radionuclide impurities) of a [61Cu]CuCl solution produced using a commercially available NatNi target on an Ag backing with that of a [61Cu]CuCl solution produced by irradiation of a Ni target electroplated according to the present disclosure on a high-purity Nb backing, as assessed by gamma spectroscopy at t=0 and t=12 hours. The presented data highlight the superior quality of the [61Cu]CuCl solution when produced by irradiation of a Ni target electroplated according to the present disclosure on a high-purity Nb backing, with the purity after 12 hours still far exceeding the purity limits set by pharmacopoeias for similar radionuclides for medical use.

[0042] [Figure 23] FIG. 10 shows chemical impurities measured by ICP-MS of [61Cu]CuCl2 solution as produced by bombardment of natNi vs. 61Ni as produced by irradiation of a Ni target electroplated according to the present disclosure onto a high purity Nb backing.

[0043] [Figure 24]Panel A shows dynamic PET / CT scans of [61Cu]Cu-NODAGA-F1 in dual HT1080.hFAP and HT1080.wt tumor-bearing mice within 1 hour, and panel B shows dynamic PET / CT scans of [61Cu]Cu-NODAGA-F3 in dual HT1080.hFAP and HT1080.wt tumor-bearing mice within 1 hour. DETAILED DESCRIPTION OF THE INVENTION

[0044] 4. Detailed Description 1.Definition When describing embodiments of the present disclosure, which may include compounds and pharmaceutically acceptable salts thereof, pharmaceutical compositions containing such compounds, and methods of using such compounds and compositions, the following terms, when present, have the following meanings unless otherwise indicated.

[0045] Generally, terms used in this specification, and particularly in the appended claims (e.g., the body of the appended claims), are generally intended as "non-limiting" terms (e.g., the term "including" should be interpreted as "including, but not limited to," the term "having" should be interpreted as "having at least," and the term "includes" should be interpreted as "including, but not limited to"). Where a specific number of introduced claim recitations are intended, such intention will be explicitly set forth in the claim; in the absence of such recitation, it will be further understood by those skilled in the art that no such intention exists. For example, to aid in understanding, the following appended claims may include the use of the introductory phrases "at least one" and "one or more" to introduce the claim recitations. However, the use of such phrases should not be interpreted as meaning that the introduction of a claim recitation with the indefinite article "a" or "an" limits any particular claim that includes such an introduced claim recitation to embodiments that include only one such recitation, even if the same claim includes the introductory phrase "one or more" or "at least one" and an indefinite article such as "a" or "an" (e.g., "a" and / or "an" should be interpreted to mean "at least one" or "one or more"). The same applies to the use of definite articles used to introduce claim recitations. Moreover, even when a specific number of introduced claim recitations is explicitly recited, those skilled in the art will recognize that such recitation should be interpreted to mean at least the recited number (e.g., a plain recitation of "two recitations" without any other modifiers means at least two recitations, or more than two recitations).Furthermore, when a convention similar to "at least one of A, B, and C, etc." is used, generally such a configuration is intended in the sense that one of ordinary skill in the art would understand the convention (e.g., "a system having at least one of A, B, and C" includes, but is not limited to, systems having A only, B only, C only, A and B together, A and C together, B and C together, and / or A, B, and C together, etc.). When a convention similar to "at least one of A, B, or C, etc." is used, generally such a configuration is intended in the sense that one of ordinary skill in the art would understand the convention (e.g., "a system having at least one of A, B, or C" includes, but is not limited to, systems having A only, B only, C only, A and B together, A and C together, B and C together, and / or A, B, and C together, etc.). It will be further understood by those skilled in the art that virtually any disjunctive word and / or phrase presenting two or more alternative terms, whether in the specification, claims, or drawings, should be understood to contemplate the possibility of including one of the terms, either of the terms, or both terms. For example, the phrase "A or B" is understood to include the possibilities of "A or B" or "A and B."

[0046] Additionally, where features or aspects of the present disclosure are described in terms of a Markush group, one of skill in the art will recognize that the present disclosure is also thereby described in terms of any individual member or subgroup of members of the Markush group.

[0047] As will be understood by those skilled in the art, for any and all purposes, e.g., with respect to providing a written description, all ranges recited herein also encompass any and all possible subranges and combinations of subranges. Any recited range can be readily recognized as fully descriptive and permitting division of the same range into at least equal halves, thirds, quarters, fifths, tenths, etc. As a non-limiting example, each range recited herein can be readily divided into a lower third, middle third, upper third, etc. Also, as will be understood by those skilled in the art, all language such as "up to," "at least," "greater than," "less than," etc., refers to a range that is inclusive of the recited numbers and can be subsequently divided into subranges as described above. Finally, as will be understood by those skilled in the art, ranges include individual members. Thus, for example, a group having 1 to 3 items refers to a group having 1, 2, or 3 items. Similarly, a group having 1 to 5 items refers to a group having 1, 2, 3, 4, or 5 items, etc.

[0048] As used herein, the term "alkyl" refers to straight and branched chain C-C alkyl groups. 30 It refers to both saturated and unsaturated hydrocarbons, e.g., "C1-C 20 The use of designations such as "alkyl" and "alkyl-" is intended to refer to an alkyl (e.g., straight or branched chain, including alkenes and alkyls) having the recited range of carbon atoms. In certain embodiments, an alkyl group has 1 to 10 carbon atoms ("C1-C 10In certain embodiments, an alkyl group has 1 to 9 carbon atoms ("C1-C9 alkyl"). In certain embodiments, an alkyl group has 1 to 8 carbon atoms ("C1-C8 alkyl"). In certain embodiments, an alkyl group has 1 to 7 carbon atoms ("C1-C7 alkyl"). In certain embodiments, an alkyl group has 1 to 6 carbon atoms ("C1-C6 alkyl"). In certain embodiments, an alkyl group has 1 to 5 carbon atoms ("C1-C5 alkyl"). In certain embodiments, an alkyl group has 1 to 4 carbon atoms ("C1-C4 alkyl"). In certain embodiments, an alkyl group has 1 to 3 carbon atoms ("C1-C3 alkyl"). In certain embodiments, an alkyl group has 1 to 2 carbon atoms ("C1-C2 alkyl"). In certain embodiments, an alkyl group has 1 carbon atom ("C1 alkyl"). Examples of C1-6 alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, and the like. Representative straight-chain alkyls include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, etc., while saturated branched alkyls include isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl, etc. Representative saturated cyclic alkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

[0049] As used herein, the term "alkenyl" refers to the radical of a straight-chain or branched hydrocarbon group having from 2 to 20 carbon atoms, one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds), and optionally one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds) ("C-C 20 In certain embodiments, an alkenyl group does not contain any triple bonds. In certain embodiments, an alkenyl group has 2 to 10 carbon atoms ("C-C 10In certain embodiments, an alkenyl group has from 2 to 9 carbon atoms ("C2-C9 alkenyl"). In certain embodiments, an alkenyl group has from 2 to 8 carbon atoms ("C2-C8 alkenyl"). In certain embodiments, an alkenyl group has from 2 to 7 carbon atoms ("C2-C7 alkenyl"). In certain embodiments, an alkenyl group has from 2 to 6 carbon atoms ("C2-C6 alkenyl"). In certain embodiments, an alkenyl group has from 2 to 5 carbon atoms ("C2-C5 alkenyl"). In certain embodiments, an alkenyl group has from 2 to 4 carbon atoms ("C2-C4 alkenyl"). In certain embodiments, an alkenyl group has 2 to 3 carbon atoms ("C2-C3 alkenyl"). In certain embodiments, an alkenyl group has 2 carbon atoms ("C2 alkenyl"). The one or more carbon-carbon double bonds can be internal (such as 2-butenyl) or terminal (such as 1-butenyl). Examples of C2-4 alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. Examples of C2-6 alkenyl groups include the aforementioned C2-4 alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Further examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like.

[0050] As used herein, the terms "alkylene," "alkenylene," and "alkynylene" refer to a divalent radical of an alkyl, alkenyl, or alkynyl group, respectively. When a range or number of carbons is provided for a particular "alkylene," "alkenylene," or "alkynylene," it is understood that the range or number refers to the range or number of carbons in a linear, divalent carbon chain. "Alkylene," "alkenylene," and "alkynylene" groups can be substituted or unsubstituted with one or more substituents described herein.

[0051] As used herein, the term "aryl" refers to aromatic groups containing 6 to 10 carbons in the ring portion (e.g., monocyclic, bicyclic, and tricyclic structures). Aryl groups may be optionally substituted through available carbon atoms and, in certain embodiments, may contain one or more heteroatoms such as oxygen, nitrogen, or sulfur. In some embodiments, an aryl group has 6 ring carbon atoms ("C6 aryl"; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms ("C 10 aryl"; for example, naphthyl such as 1-naphthyl and 2-naphthyl).

[0052] As used herein, the terms "chelating moiety" and "chelator" are used interchangeably in the context of this disclosure and refer to a molecule, often an organic molecule, and often a Lewis base, that has two or more unshared electron pairs available for donation to a metal ion. The metal ion is typically coordinated to the chelating moiety by two or more electron pairs. The terms "bidentate chelating moiety," "tridentate chelating moiety," and "tetradentate chelating moiety" refer to chelating moieties that have two, three, and four electron pairs readily available for simultaneous donation to the metal ion coordinated by the chelating moiety, respectively. Typically, the electron pairs of the chelating moiety form coordinate bonds with a single metal ion. However, in certain instances, the chelating moiety may form coordinate bonds with more than one metal ion, allowing for various binding modes.

[0053] With respect to chemical structures involving chelated metals, the depicted structures are not intended to define the coordination sphere. Furthermore, the presence or absence of a proton on the ionizable binding moiety is not intended to be determinative. One skilled in the art can determine the coordination sphere, oxidation state, and degree of ionization, as the case may be.

[0054] As used herein, the terms "effective amount," "pharmaceutical effective amount," or "therapeutically effective amount" refer to a compound or composition in an amount sufficient to provide a desired benefit when administered to a subject. Thus, the term "therapeutically effective amount" refers to an amount of a compound or composition sufficient to promote a particular effect when administered to a subject in need of treatment. In certain embodiments, an effective amount includes an amount of a compound or composition sufficient to prevent or delay the onset of disease symptoms, alter the course of disease symptoms (e.g., but not limited to, slowing the progression of disease symptoms), or reverse disease symptoms. In certain embodiments, an effective amount includes an amount of a compound or composition sufficient to generate an image of a subject. In certain embodiments, an effective amount includes an amount of a compound or composition sufficient to diagnose a disease in a subject. It is understood that for any given case, an appropriate "effective amount" can be determined by one of ordinary skill in the art using routine experimentation. For example, when administered clinically, such a compound or composition contains an amount of active ingredient effective to achieve a desired result (e.g., imaging cancerous tissue and / or reducing the amount of cancerous tissue in a subject).

[0055] As used herein, "halo" and "halogen" refer to an atom selected from fluorine (fluoro, F), chlorine (chloro, Cl), bromine (bromo, Br), and iodine (iodo, I).

[0056] As used herein, "heteroaryl" refers to a radical of a 5- to 10-membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 electrons shared within the cyclic array) having ring carbon atoms and 1 to 4 ring heteroatoms provided to the aromatic ring system, each heteroatom being independently selected from nitrogen, oxygen, and sulfur ("5- to 10-membered heteroaryl"). In heteroaryl groups containing one or more nitrogen atoms, the point of attachment can be a carbon atom or a nitrogen atom, valence permitting. Heteroaryl bicyclic ring systems can contain one or more heteroatoms in one or both rings. "Heteroaryl" includes ring systems in which a heteroaryl ring, as defined above, is fused to one or more carbocyclyl or heterocyclyl groups, and the point of attachment is on the heteroaryl ring; in such cases, the number of ring members continues to designate the number of ring members in the heteroaryl ring system. "Heteroaryl" also includes ring systems in which a heteroaryl ring, as defined above, is fused to one or more aryl groups, and the point of attachment is on either the aryl or heteroaryl ring; in such cases, the number of ring members designates the number of ring members in the fused (aryl / heteroaryl) ring system. For bicyclic heteroaryl groups in which one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, etc.), the point of attachment can be on either ring, i.e., the ring with a heteroatom (e.g., 2-indolyl) or the ring without a heteroatom (e.g., 5-indolyl).

[0057] As used herein, the term "heterocyclyl" or "heterocyclic" refers to a radical of a 3- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, each independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("3- to 10-membered heterocyclyl"). In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment can be a carbon atom or a nitrogen atom, valence permitting. Heterocyclyl groups can be either monocyclic ("monocyclic heterocyclyl") or fused, bridged, or spiro ring systems, e.g., bicyclic systems ("bicyclic heterocyclyl"), and can be saturated or partially unsaturated. Heterocyclyl bicyclic ring systems can contain one or more heteroatoms in one or both rings. "Heterocyclyl" also includes ring systems in which a heterocyclyl ring, as defined above, is fused to one or more carbocyclyl groups, and the point of attachment is on either the carbocyclyl or the heterocyclyl ring, or in which a heterocyclyl ring, as defined above, is fused to one or more aryl or heteroaryl groups, and the point of attachment is on the heterocyclyl ring, in which case the number of ring members continues to specify the number of ring members in the heterocyclyl ring system. The terms "heterocycle," "heterocyclyl," "heterocyclyl ring," "heterocyclic group," "heterocyclic moiety," and "heterocyclic group" may be used interchangeably. Heterocycles include morpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, piperidinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydroprimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like.

[0058] As used herein, the term "pharmaceutically acceptable salt" refers to a salt that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, etc., and that is commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66:1-19. Pharmaceutically acceptable salts of the compounds of the present disclosure include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts include salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentane-propionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, Included are lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, picrate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N(C1-4 alkyl)4 salts.Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Further pharmaceutically acceptable salts include, where appropriate, non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkylsulfonates, and arylsulfonates.

[0059] As used herein, the term "radioactive moiety" refers to a molecular assembly that carries a radionuclide, the nuclide being attached by a covalent or coordinate bond, or a combination thereof, that remains stable under physiological conditions.

[0060] As used herein, "radioisotope" refers to a radioactive isotope of an element (included in the term "radionuclide") that emits, for example, alpha, beta, and / or gamma radiation.

[0061] As used herein, "radiotracer" refers to a compound of the present disclosure that contains a radionuclide or radioisotope. The radionuclide can be chelated to a chelating moiety that is a covalent component of the radiotracer, or the radionuclide itself can be a covalent component of the radiotracer. As used herein, a compound, e.g., a radiotracer, refers to a compound that contains a particular radioisotope or radionuclide (e.g., 61 When a compound is described as containing Cu), it is understood that the compound is isotopically enriched with that isotope at the indicated position.

[0062] As used herein, the term "substituted," whether preceded by the term "optionally" or not, means that at least one hydrogen present on the group (e.g., a hydrogen bonded to a carbon or nitrogen atom of the group) is replaced with an acceptable substituent, e.g., a substituent that, upon substitution, results in a stable compound, e.g., a compound that does not spontaneously undergo transformation by rearrangement, cyclization, elimination, or other reaction. Unless otherwise indicated, a "substituted" group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent may be the same or different at each position.

[0063] When a range of values ​​is listed, it is intended to encompass each value and subrange within that range. For example, "C1-C6 alkyl" is intended to include C1, C2, C3, C4, C5, C6, C1-C6, C1-C5, C1-C4, C1-C3, C1-C2, C2-C6, C2-C5, C2-C4, C2-C3, C3-C6, C3-C5, C3-C4, C4-C6, C4-C5 and C5-C6 alkyl.

[0064] In typical embodiments, the present disclosure is intended to encompass the compounds disclosed herein, as well as pharmaceutically acceptable salts, pharmaceutically acceptable esters, tautomers, polymorphs, and prodrugs of such compounds. In certain embodiments, the present disclosure includes pharmaceutically acceptable addition salts, pharmaceutically acceptable esters, solvates (e.g., hydrates) of addition salts, tautomers, polymorphs, enantiomers, mixtures of enantiomers, stereoisomers, or mixtures of stereoisomers (pure or as racemic or non-racemic mixtures) of the compounds described herein.

[0065] The compounds described herein may contain one or more asymmetric centers and therefore may exist in various isomeric forms, such as enantiomers and / or diastereomers. For example, the compounds described herein may be in the form of individual enantiomers, diastereomers, or geometric isomers, or may be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high-pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts. Alternatively, preferred isomers can be prepared by asymmetric synthesis. See, for example, Jacques et al., "Enantiomers, Racemates and Resolutions" (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, "Stereochemistry of Carbon Compounds" (McGraw-Hill, NY, 1962); and Wilen, "Tables of Resolving Agents and Optical Resolutions," p. 268 (EL Eliel, Ed., University of Notre Dame Press, Notre Dame, IN 1972). The present disclosure further encompasses the compounds described herein as individual isomers substantially free of other isomers or as mixtures of various isomers.

[0066] 2.Compound In one aspect, the present disclosure provides FAP inhibitor compounds, and compounds (also referred to as "conjugates") comprising novel FAP inhibitors. The FAP inhibitors and their conjugates can be used in the diagnosis and treatment of diseases characterized by the expression of FAP.

[0067] The present disclosure provides a compound, the compound being a compound of formula I: [ka] R 1 is R a and; R 2 and R 3 are R a or together with the nitrogen atom to which they are attached and C 2-9 Forming a heterocyclic ring; R 4 is H, an amine protecting group, or -LT; R a independently for each occurrence, H, C 1-10 Alkyl, C 2-10 Alkenyl, C 3-10 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, C 2-9 Heterocyclyl, or C 5-9 heteroaryl, optionally substituted with one or more substituents selected from —OH, —OR′, ═O, ═S, —SH, —SR′, —NH, —NHR′, —N(R′) , —NHCOR′, —NR′COR′, halogen, —CN, —COH, —COR′, —CHO, —COR′, —CONH, —CONHR′, —CON(R′) , —NO , —OP(O)(OH) , —SOH, —SOR′, —SOR′, and —SOR′; R′ is independently for each occurrence C 1-10 Alkyl or C 3-10 is cycloalkyl; L is a bond or a bivalent linker; T comprises (a) a chelating moiety suitable for chelating a radionuclide, (b) an imaging agent, or (c) a drug; n is an integer from 1 to 20; m is an integer from 1 to 20; or a pharmaceutically acceptable salt thereof.

[0068] In certain embodiments of Formula I, R 1 is H. In certain embodiments of Formula I, R 1 is C 1-10 Alkyl, C2-10 Alkenyl, C 3-10 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, C 2-9 Heterocyclyl, or C 5-9 heteroaryl, optionally substituted with one or more substituents selected from —OH, —OR′, ═O, ═S, —SH, —SR′, —NH, —NHR′, —N(R′) , —NHCOR′, —NR′COR′, halogen, —CN, —COH, —COR′, —CHO, —COR′, —CONH, —CONHR′, —CON(R′) , —NO , —OP(O)(OH) , —SOH, —SOR′, —SOR′, and —SOR′; R′ is independently for each occurrence C 1-10 Alkyl or C 3-10 In certain embodiments of Formula I, R 1 is H,C 1-10 Alkyl, C 2-10 Alkenyl, C 3-10 Alkynyl, C 3-10 cycloalkyl, optionally substituted with one or more substituents selected from —OH, —OR′, ═O, ═S, —SH, —SR′, —NH, —NHR′, —N(R′) , —NHCOR′, —NR′COR′, halogen, —CN, —COH, —COR′, —CHO, —COR′, —CONH, —CONHR′, —CON(R′) , —NO , —OP(O)(OH) , —SOH, —SOR′, —SOR′, and —SOR′, wherein R′ is independently for each occurrence C 1-10 Alkyl or C 3-10 It is cycloalkyl.

[0069] In certain embodiments of Formula I, R 1 is H and C 1-10 In certain embodiments of Formula I, R 1 is H. In certain embodiments of Formula I, R 1 is C 1-10 In certain embodiments of Formula I, R 1is C1-C6 alkyl. In certain embodiments of Formula I, R is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, and hexyl. In certain embodiments of Formula I, R 1 is methyl.

[0070] In certain embodiments of Formula I, R 2 is H. In certain embodiments of Formula I, R 2 is C 1-10 Alkyl, C 2-10 Alkenyl, C 3-10 Alkynyl, C 3-10 cycloalkyl, optionally substituted with one or more substituents selected from —OH, —OR′, ═O, ═S, —SH, —SR′, —NH, —NHR′, —N(R′) , —NHCOR′, —NR′COR′, halogen, —CN, —COH, —COR′, —CHO, —COR′, —CONH, —CONHR′, —CON(R′) , —NO , —OP(O)(OH) , —SOH, —SOR′, —SOR′, and —SOR′, wherein R′ is independently for each occurrence C 1-10 Alkyl or C 3-10 It is cycloalkyl.

[0071] In certain embodiments of Formula I, R 3 is H. In certain embodiments of Formula I, R 3 is C 1-10 Alkyl, C 2-10 Alkenyl, C 3-10 Alkynyl, C 3-10 cycloalkyl, optionally substituted with one or more substituents selected from —OH, —OR′, ═O, ═S, —SH, —SR′, —NH, —NHR′, —N(R′) , —NHCOR′, —NR′COR′, halogen, —CN, —COH, —COR′, —CHO, —COR′, —CONH, —CONHR′, —CON(R′) , —NO , —OP(O)(OH) , —SOH, —SOR′, —SOR′, and —SOR′, wherein R′ is independently for each occurrence C 1-10 Alkyl or C 3-10 It is cycloalkyl.

[0072] In certain embodiments of Formula I, R 2 and R 3 together with the nitrogen atom to which they are attached and C 2-9 In certain embodiments of Formula I, C 2-9 The heterocycle is a 5-, 6-, or 7-membered heterocycle. In certain embodiments of Formula I, C 2-9 The heterocycle is a 5-membered heterocycle selected from pyrrolidine, pyrazolidine, and imidazoline. 2-9 The heterocycle is a 6-membered heterocycle selected from piperazine, hexahydropyrimidine, hexahydropyridazine, 1,2,3-triazinane, 1,2,4-triazinane, and 1,3,5-triazinane. In certain embodiments of Formula I, C 2-9 The heterocycle is piperazine.

[0073] In certain embodiments of Formula I, R 4 is H.

[0074] In certain embodiments of Formula I, R 4 is an amine protecting group. In certain embodiments, the amine protecting group is selected from carbobenzyloxy (Cbz), p-methoxybenzylcarbonyl (Moz or MeOZ), tert-butyloxycarbonyl (Boc), 9-fluorenylmethyloxycarbonyl (FMOC), acetyl (Ac), benzoyl (Bz), benzyl (Bn), carbamate, p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), succinimide (i.e., cyclic imide), and tosyl (Ts). In certain embodiments of Formula I, the amine protecting group is Boc.

[0075] In certain embodiments of Formula I, R 4 is -LT.

[0076] In certain embodiments of Formula I, n is an integer from 1 to 10. In certain embodiments of Formula I, n is an integer from 1 to 5. In certain embodiments of Formula I, n is 1, 2, 3, 4, or 5. In certain embodiments of Formula I, n is 2.

[0077] In certain embodiments of Formula I, m is an integer from 1 to 10. In certain embodiments of Formula I, m is an integer from 1 to 5. In certain embodiments of Formula I, m is 1, 2, 3, 4, or 5. In certain embodiments of Formula I, m is 2.

[0078] In certain embodiments of Formula I, R 1 is H and C 1-10 alkyl, and R 2 is H and R 3 is H and R 4 is H, n is an integer from 1 to 20, and m is an integer from 1 to 20. In certain embodiments of Formula I, R 1 is H and C 1-10 alkyl, and R 2 is H and R 3 is H and R 4 is H, n is an integer from 1 to 10, and m is an integer from 1 to 10. In certain embodiments of Formula I, R 1 is H and C 1-10 alkyl, and R 2 is H and R 3 is H and R 4 is H, n is an integer from 1 to 5, and m is an integer from 1 to 5. In certain embodiments of Formula I, R 1 is H and C 1-10 alkyl, and R 2 is H and R 3 is H and R 4 is H, n is 2, and m is 2.

[0079] In certain embodiments of Formula I, R 1 is H and C 1-10 alkyl, and R 2 is H and R 3 is H and R 4is an amine protecting group, n is an integer from 1 to 20, and m is an integer from 1 to 20. In certain embodiments of Formula I, R 1 is H and C 1-10 alkyl, and R 2 is H and R 3 is H and R 4 is an amine protecting group, n is an integer from 1 to 10, and m is an integer from 1 to 10. In certain embodiments of Formula I, R 1 is H and C 1-10 alkyl, and R 2 is H and R 3 is H and R 4 is an amine protecting group, n is an integer from 1 to 5, and m is an integer from 1 to 5. In certain embodiments of Formula I, R 1 is H and C 1-10 alkyl, and R 2 is H and R 3 is H and R 4 is an amine protecting group, n is 2, and m is 2.

[0080] In certain embodiments of Formula I, R 1 is H and C 1-10 alkyl, and R 2 is H and R 3 is H and R 4 is -LT, n is an integer from 1 to 20, and m is an integer from 1 to 20. In certain embodiments of Formula I, R 1 is H and C 1-10 alkyl, and R 2 is H and R 3 is H and R 4 is -LT, n is an integer from 1 to 10, and m is an integer from 1 to 10. In certain embodiments of Formula I, R 1 is H and C 1-10 alkyl, and R 2 is H and R 3 is H and R 4 is -LT, n is an integer from 1 to 5, and m is an integer from 1 to 5. In certain embodiments of Formula I, R 1 is H and C 1-10alkyl, and R 2 is H and R 3 is H and R 4 is -LT, n is 2, and m is 2.

[0081] In certain embodiments of Formula I, R 1 is H and C 1-10 alkyl, and R 2 and R 3 together with the nitrogen atom to which they are attached and C 2-9 form a heterocyclic ring, R 4 is H, n is an integer from 1 to 20, and m is an integer from 1 to 20. In certain embodiments of Formula I, R 1 is H and C 1-10 alkyl, and R 2 and R 3 together with the nitrogen atom to which they are attached and C 2-9 form a heterocyclic ring, R 4 is H, n is an integer from 1 to 10, and m is an integer from 1 to 10. In certain embodiments of Formula I, R 1 is H and C 1-10 alkyl, and R 2 and R 3 together with the nitrogen atom to which they are attached and C 2-9 form a heterocyclic ring, R 4 is H, n is an integer from 1 to 5, and m is an integer from 1 to 5. In certain embodiments of Formula I, R 1 is H and C 1-10 alkyl, and R 2 and R 3 together with the nitrogen atom to which they are attached and C 2-9 form a heterocyclic ring, R 4 is H, n is 2, and m is 2.

[0082] In certain embodiments of Formula I, R 1 is H and C 1-10 alkyl, and R 2 and R 3 together with the nitrogen atom to which they are attached and C 2-9form a heterocyclic ring, R 4 is an amine protecting group, n is an integer from 1 to 20, and m is an integer from 1 to 20. In certain embodiments of Formula I, R 1 is H and C 1-10 alkyl, and R 2 and R 3 together with the nitrogen atom to which they are attached and C 2-9 form a heterocyclic ring, R 4 is an amine protecting group, n is an integer from 1 to 10, and m is an integer from 1 to 10. In certain embodiments of Formula I, R 1 is H and C 1-10 alkyl, and R 2 and R 3 together with the nitrogen atom to which they are attached and C 2-9 form a heterocyclic ring, R 4 is an amine protecting group, n is an integer from 1 to 5, and m is an integer from 1 to 5. In certain embodiments of Formula I, R 1 is H and C 1-10 alkyl, and R 2 and R 3 together with the nitrogen atom to which they are attached and C 2-9 form a heterocyclic ring, R 4 is an amine protecting group, n is 2, and m is 2.

[0083] In certain embodiments of Formula I, R 1 is H and C 1-10 alkyl, and R 2 and R 3 together with the nitrogen atom to which they are attached and C 2-9 form a heterocyclic ring, R 4 is -LT, n is an integer from 1 to 20, and m is an integer from 1 to 20. In certain embodiments of Formula I, R 1 is H and C 1-10 alkyl, and R 2 and R 3 together with the nitrogen atom to which they are attached and C 2-9 form a heterocyclic ring, R 4is -LT, n is an integer from 1 to 10, and m is an integer from 1 to 10. In certain embodiments of Formula I, R 1 is H and C 1-10 alkyl, and R 2 and R 3 together with the nitrogen atom to which they are attached and C 2-9 form a heterocyclic ring, R 4 is -LT, n is an integer from 1 to 5, and m is an integer from 1 to 5. In certain embodiments of Formula I, R 1 is H and C 1-10 alkyl, and R 2 and R 3 together with the nitrogen atom to which they are attached and C 2-9 form a heterocyclic ring, R 4 is -LT, n is 2, and m is 2.

[0084] In certain embodiments of Formula I, R 1 is H and C 1-10 alkyl, and R 2 and R 3 together with the nitrogen atom to which they are attached and C 2-9 Forming a heterocyclic ring, C 2-9 The heterocycle is a 5-, 6-, or 7-membered heterocycle, and R 4 is H, n is an integer from 1 to 20, and m is an integer from 1 to 20. In certain embodiments of Formula I, R 1 is H and C 1-10 alkyl, and R 2 and R 3 together with the nitrogen atom to which they are attached and C 2-9 Forming a heterocyclic ring, C 2-9 The heterocycle is a 5-, 6-, or 7-membered heterocycle, and R 4 is H, n is an integer from 1 to 10, and m is an integer from 1 to 10. In certain embodiments of Formula I, R 1 is H and C 1-10 alkyl, and R 2 and R 3 together with the nitrogen atom to which they are attached and C 2-9 Forming a heterocyclic ring, C 2-9The heterocycle is a 5-, 6-, or 7-membered heterocycle, and R 4 is H, n is an integer from 1 to 5, and m is an integer from 1 to 5. In certain embodiments of Formula I, R 1 is H and C 1-10 alkyl, and R 2 and R 3 together with the nitrogen atom to which they are attached and C 2-9 Forming a heterocyclic ring, C 2-9 The heterocycle is a 5-, 6-, or 7-membered heterocycle, and R 4 is H, n is 2, and m is 2.

[0085] In certain embodiments of Formula I, R 1 is H and C 1-10 alkyl, and R 2 and R 3 together with the nitrogen atom to which they are attached and C 2-9 Forming a heterocyclic ring, C 2-9 The heterocycle is a 5-, 6-, or 7-membered heterocycle, and R 4 is an amine protecting group, n is an integer from 1 to 20, and m is an integer from 1 to 20. In certain embodiments of Formula I, R 1 is H and C 1-10 alkyl, and R 2 and R 3 together with the nitrogen atom to which they are attached and C 2-9 Forming a heterocyclic ring, C 2-9 The heterocycle is a 5-, 6-, or 7-membered heterocycle, and R 4 is an amine protecting group, n is an integer from 1 to 10, and m is an integer from 1 to 10. In certain embodiments of Formula I, R 1 is H and C 1-10 alkyl, and R 2 and R 3 together with the nitrogen atom to which they are attached and C 2-9 Forming a heterocyclic ring, C 2-9 The heterocycle is a 5-, 6-, or 7-membered heterocycle, and R 4 is an amine protecting group, n is an integer from 1 to 5, and m is an integer from 1 to 5. In certain embodiments of Formula I, R 1 is H and C1-10 alkyl, and R 2 and R 3 together with the nitrogen atom to which they are attached and C 2-9 Forming a heterocyclic ring, C 2-9 The heterocycle is a 5-, 6-, or 7-membered heterocycle, and R 4 is an amine protecting group, n is 2, and m is 2.

[0086] In certain embodiments of Formula I, R 1 is H and C 1-10 alkyl, and R 2 and R 3 together with the nitrogen atom to which they are attached and C 2-9 Forming a heterocyclic ring, C 2-9 The heterocycle is a 5-, 6-, or 7-membered heterocycle, and R 4 is -LT, n is an integer from 1 to 20, and m is an integer from 1 to 20. In certain embodiments of Formula I, R 1 is H and C 1-10 alkyl, and R 2 and R 3 together with the nitrogen atom to which they are attached and C 2-9 Forming a heterocyclic ring, C 2-9 The heterocycle is a 5-, 6-, or 7-membered heterocycle, and R 4 is -LT, n is an integer from 1 to 10, and m is an integer from 1 to 10. In certain embodiments of Formula I, R 1 is H and C 1-10 alkyl, and R 2 and R 3 together with the nitrogen atom to which they are attached and C 2-9 Forming a heterocyclic ring, C 2-9 The heterocycle is a 5-, 6-, or 7-membered heterocycle, and R 4 is -LT, n is an integer from 1 to 5, and m is an integer from 1 to 5. In certain embodiments of Formula I, R 1 is H and C 1-10 alkyl, and R 2 and R 3 together with the nitrogen atom to which they are attached and C 2-9 Forming a heterocyclic ring, C2-9 The heterocycle is a 5-, 6-, or 7-membered heterocycle, and R 4 is -LT, n is 2, and m is 2.

[0087] In certain embodiments of Formula I, R 1 is H and C 1-10 alkyl, and R 2 and R 3 together with the nitrogen atom to which they are attached and C 2-9 Forming a heterocyclic ring, C 2-9 The heterocycle is a six-membered heterocycle, and R 4 is H, n is an integer from 1 to 20, and m is an integer from 1 to 20. In certain embodiments of Formula I, R 1 is H and C 1-10 alkyl, and R 2 and R 3 together with the nitrogen atom to which they are attached and C 2-9 Forming a heterocyclic ring, C 2-9 The heterocycle is a six-membered heterocycle, and R 4 is H, n is an integer from 1 to 10, and m is an integer from 1 to 10. In certain embodiments of Formula I, R 1 is H and C 1-10 alkyl, and R 2 and R 3 together with the nitrogen atom to which they are attached and C 2-9 Forming a heterocyclic ring, C 2-9 The heterocycle is a six-membered heterocycle, and R 4 is H, n is an integer from 1 to 5, and m is an integer from 1 to 5. In certain embodiments of Formula I, R 1 is H and C 1-10 alkyl, and R 2 and R 3 together with the nitrogen atom to which they are attached and C 2-9 Forming a heterocyclic ring, C 2-9 The heterocycle is a six-membered heterocycle, and R 4 is H, n is 2, and m is 2.

[0088] In certain embodiments of Formula I, R 1 is H and C1-10 alkyl, and R 2 and R 3 together with the nitrogen atom to which they are attached and C 2-9 Forming a heterocyclic ring, C 2-9 The heterocycle is a six-membered heterocycle, and R 4 is an amine protecting group, n is an integer from 1 to 20, and m is an integer from 1 to 20. In certain embodiments of Formula I, R 1 is H and C 1-10 alkyl, and R 2 and R 3 together with the nitrogen atom to which they are attached and C 2-9 Forming a heterocyclic ring, C 2-9 The heterocycle is a six-membered heterocycle, and R 4 is an amine protecting group, n is an integer from 1 to 10, and m is an integer from 1 to 10. In certain embodiments of Formula I, R 1 is H and C 1-10 alkyl, and R 2 and R 3 together with the nitrogen atom to which they are attached and C 2-9 Forming a heterocyclic ring, C 2-9 The heterocycle is a six-membered heterocycle, and R 4 is an amine protecting group, n is an integer from 1 to 5, and m is an integer from 1 to 5. In certain embodiments of Formula I, R 1 is H and C 1-10 alkyl, and R 2 and R 3 together with the nitrogen atom to which they are attached and C 2-9 Forming a heterocyclic ring, C 2-9 The heterocycle is a six-membered heterocycle, and R 4 is an amine protecting group, n is 2, and m is 2.

[0089] In certain embodiments of Formula I, R 1 is H and C 1-10 alkyl, and R 2 and R 3 together with the nitrogen atom to which they are attached and C 2-9 Forming a heterocyclic ring, C 2-9 The heterocycle is a six-membered heterocycle, and R4 is -LT, n is an integer from 1 to 20, and m is an integer from 1 to 20. In certain embodiments of Formula I, R 1 is H and C 1-10 alkyl, and R 2 and R 3 together with the nitrogen atom to which they are attached and C 2-9 Forming a heterocyclic ring, C 2-9 The heterocycle is a six-membered heterocycle, and R 4 is -LT, n is an integer from 1 to 10, and m is an integer from 1 to 10. In certain embodiments of Formula I, R 1 is H and C 1-10 alkyl, and R 2 and R 3 together with the nitrogen atom to which they are attached and C 2-9 Forming a heterocyclic ring, C 2-9 The heterocycle is a six-membered heterocycle, and R 4 is -LT, n is an integer from 1 to 5, and m is an integer from 1 to 5. In certain embodiments of Formula I, R 1 is H and C 1-10 alkyl, and R 2 and R 3 together with the nitrogen atom to which they are attached and C 2-9 Forming a heterocyclic ring, C 2-9 The heterocycle is a six-membered heterocycle, and R 4 is -LT, n is 2, and m is 2.

[0090] In certain embodiments of Formula I, R 1 is H and C 1-10 alkyl, and R 2 and R 3 together with the nitrogen atom to which they are attached and C 2-9 Forming a heterocyclic ring, C 2-9 The heterocycle is piperazine, and R 4 is H, m is an integer from 1 to 20, and n is an integer from 1 to 20. In certain embodiments of Formula I, R 1 is H and C 1-10 alkyl, and R 2 and R 3together with the nitrogen atom to which they are attached and C 2-9 Forming a heterocyclic ring, C 2-9 The heterocycle is piperazine, and R 4 is H, m is an integer from 1 to 10, and n is an integer from 1 to 10. In certain embodiments of Formula I, R 1 is H and C 1-10 alkyl, and R 2 and R 3 together with the nitrogen atom to which they are attached and C 2-9 Forming a heterocyclic ring, C 2-9 The heterocycle is piperazine, and R 4 is H, m is an integer from 1 to 5, and n is an integer from 1 to 5. In certain embodiments of Formula I, R 1 is H and C 1-10 alkyl, and R 2 and R 3 together with the nitrogen atom to which they are attached and C 2-9 Forming a heterocyclic ring, C 2-9 The heterocycle is piperazine, and R 4 is H, m is 2, and n is 2.

[0091] In certain embodiments of Formula I, R 1 is H and C 1-10 alkyl, and R 2 and R 3 together with the nitrogen atom to which they are attached and C 2-9 Forming a heterocyclic ring, C 2-9 The heterocycle is piperazine, and R 4 is an amine protecting group, m is an integer from 1 to 20, and n is an integer from 1 to 20. In certain embodiments of Formula I, R 1 is H and C 1-10 alkyl, and R 2 and R 3 together with the nitrogen atom to which they are attached and C 2-9 Forming a heterocyclic ring, C 2-9 The heterocycle is piperazine, and R 4 is an amine protecting group, m is an integer from 1 to 10, and n is an integer from 1 to 10. In certain embodiments of Formula I, R1 is H and C 1-10 alkyl, and R 2 and R 3 together with the nitrogen atom to which they are attached and C 2-9 Forming a heterocyclic ring, C 2-9 The heterocycle is piperazine, and R 4 is an amine protecting group, m is an integer from 1 to 5, and n is an integer from 1 to 5. In certain embodiments of Formula I, R 1 is H and C 1-10 alkyl, and R 2 and R 3 together with the nitrogen atom to which they are attached and C 2-9 Forming a heterocyclic ring, C 2-9 The heterocycle is piperazine, and R 4 is an amine protecting group, m is 2, and n is 2.

[0092] In certain embodiments of Formula I, R 1 is H and C 1-10 alkyl, and R 2 and R 3 together with the nitrogen atom to which they are attached and C 2-9 Forming a heterocyclic ring, C 2-9 The heterocycle is piperazine, and R 4 is -LT, m is an integer from 1 to 20, and n is an integer from 1 to 20. In certain embodiments of Formula I, R 1 is H and C 1-10 alkyl, and R 2 and R 3 together with the nitrogen atom to which they are attached and C 2-9 Forming a heterocyclic ring, C 2-9 The heterocycle is piperazine, and R 4 is -LT, m is an integer from 1 to 10, and n is an integer from 1 to 10. In certain embodiments of Formula I, R 1 is H and C 1-10 alkyl, and R 2 and R 3 together with the nitrogen atom to which they are attached and C 2-9 Forming a heterocyclic ring, C 2-9The heterocycle is piperazine, and R 4 is -LT, m is an integer from 1 to 5, and n is an integer from 1 to 5. In certain embodiments of Formula I, R 1 is H and C 1-10 alkyl, and R 2 and R 3 together with the nitrogen atom to which they are attached and C 2-9 Forming a heterocyclic ring, C 2-9 The heterocycle is piperazine, and R 4 is -LT, m is 2, and n is 2.

[0093] In certain embodiments of Formula I, R 2 and R 3 taken together with the nitrogen atom to which they are attached form a piperazine, and m is 2, thereby providing a compound of formula Ia: [ka] or a pharmaceutically acceptable salt thereof, 1 , R 4 and n is as described above for Formula I.

[0094] In certain embodiments of Formula Ia, R 1 is H. In certain embodiments of Formula Ia, R 1 is C 1-10 Alkyl, C 2-10 Alkenyl, C 3-10 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, C 2-9 Heterocyclyl, or C 5-9heteroaryl, optionally substituted with one or more substituents selected from —OH, —OR′, ═O, ═S, —SH, —SR′, —NH, —NHR′, —N(R′) , —NHCOR′, —NR′COR′, halogen, —CN, —COH, —COR′, —CHO, —COR′, —CONH, —CONHR′, —CON(R′) , —NO , —OP(O)(OH) , —SOH, —SOR′, —SOR′, and —SOR′; R′ is independently for each occurrence C 1-10 Alkyl or C 3-10 It is cycloalkyl.

[0095] In certain embodiments of Formula Ia, R 1 is H,C 1-10 Alkyl, C 2-10 Alkenyl, C 3-10 Alkynyl, C 3-10 cycloalkyl, optionally substituted with one or more substituents selected from —OH, —OR′, ═O, ═S, —SH, —SR′, —NH, —NHR′, —N(R′) , —NHCOR′, —NR′COR′, halogen, —CN, —COH, —COR′, —CHO, —COR′, —CONH, —CONHR′, —CON(R′) , —NO , —OP(O)(OH) , —SOH, —SOR′, —SOR′, and —SOR′, wherein R′ is independently for each occurrence C 1-10 Alkyl or C 3-10 It is cycloalkyl.

[0096] In certain embodiments of Formula Ia, R 1 is H and C 1-10 In certain embodiments of Formula Ia, R 1 is H. In certain embodiments of Formula Ia, R 1 is C 1-10 In certain embodiments of Formula Ia, R 1 is C1-C6 alkyl. In certain embodiments of Formula Ia, R is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, and hexyl. In certain embodiments of Formula Ia, R 1 is methyl.

[0097] In certain embodiments of Formula Ia, R 4 is H.

[0098] In certain embodiments of Formula Ia, R 4 is an amine protecting group. In certain embodiments of Formula Ia, the amine protecting group is selected from carbobenzyloxy (Cbz), p-methoxybenzylcarbonyl (Moz or MeOZ), tert-butyloxycarbonyl (Boc), 9-fluorenylmethyloxycarbonyl (FMOC), acetyl (Ac), benzoyl (Bz), benzyl (Bn), carbamate, p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), succinimide (i.e., cyclic imide), and tosyl (Ts). In certain embodiments of Formula Ia, the amine protecting group is Boc.

[0099] In certain embodiments of Formula Ia, R 4 is -LT.

[0100] In certain embodiments of Formula Ia, n is an integer from 1 to 10. In certain embodiments of Formula Ia, n is an integer from 1 to 5. In certain embodiments of Formula Ia, n is 1, 2, 3, 4, or 5. In certain embodiments of Formula Ia, n is 2.

[0101] In certain embodiments of Formula Ia, R 1 is H and C 1-10 alkyl, and R 4 is H and n is an integer from 1 to 20. In certain embodiments of Formula Ia, R 1 is H and C 1-10 alkyl, and R 4 is H and n is an integer from 1 to 10. In certain embodiments of Formula Ia, R 1 is H and C 1-10 alkyl, and R 4 is H and n is an integer from 1 to 5. In certain embodiments of Formula Ia, R 1 is H and C 1-10alkyl, and R 4 is H and n is 2.

[0102] In certain embodiments of Formula Ia, R 1 is H and C 1-10 alkyl, and R 4 is an amine protecting group and n is an integer from 1 to 20. In certain embodiments of Formula Ia, R 1 is H and C 1-10 alkyl, and R 4 is an amine protecting group and n is an integer from 1 to 10. In certain embodiments of Formula Ia, R 1 is H and C 1-10 alkyl, and R 4 is an amine protecting group and n is an integer from 1 to 5. In certain embodiments of Formula Ia, R 1 is H and C 1-10 alkyl, and R 4 is an amine protecting group and n is 2.

[0103] In certain embodiments of Formula Ia, R 1 is H and C 1-10 alkyl, and R 4 is -LT and n is an integer from 1 to 20. In certain embodiments of Formula Ia, R 1 is H and C 1-10 alkyl, and R 4 is -LT and n is an integer from 1 to 10. In certain embodiments of Formula Ia, R 1 is H and C 1-10 alkyl, and R 4 is -LT and n is an integer from 1 to 5. In certain embodiments of Formula Ia, R 1 is H and C 1-10 alkyl, and R 4 is -LT and n is 2.

[0104] In certain embodiments of Formula I, R 2 and R 3 is H and m is 2, thereby providing a compound of formula Ib: [ka] or a pharmaceutically acceptable salt thereof, 1 , R 4 and n is as described above for Formula I.

[0105] In certain embodiments of Formula Ib, R 1 is H. In certain embodiments of Formula Ib, R 1 is C 1-10 Alkyl, C 2-10 Alkenyl, C 3-10 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, C 2-9 Heterocyclyl, or C 5-9 heteroaryl, optionally substituted with one or more substituents selected from —OH, —OR′, ═O, ═S, —SH, —SR′, —NH, —NHR′, —N(R′) , —NHCOR′, —NR′COR′, halogen, —CN, —COH, —COR′, —CHO, —COR′, —CONH, —CONHR′, —CON(R′) , —NO , —OP(O)(OH) , —SOH, —SOR′, —SOR′, and —SOR′; R′ is independently for each occurrence C 1-10 Alkyl or C 3-10 It is cycloalkyl.

[0106] In certain embodiments of Formula Ib, R 1 is H,C 1-10 Alkyl, C 2-10 Alkenyl, C 3-10 Alkynyl, C 3-10cycloalkyl, optionally substituted with one or more substituents selected from —OH, —OR′, ═O, ═S, —SH, —SR′, —NH, —NHR′, —N(R′) , —NHCOR′, —NR′COR′, halogen, —CN, —COH, —COR′, —CHO, —COR′, —CONH, —CONHR′, —CON(R′) , —NO , —OP(O)(OH) , —SOH, —SOR′, —SOR′, and —SOR′, wherein R′ is independently for each occurrence C 1-10 Alkyl or C 3-10 It is cycloalkyl.

[0107] In certain embodiments of Formula Ib, R 1 is H and C 1-10 In certain embodiments of Formula Ib, R 1 is H. In certain embodiments of Formula Ib, R 1 is C 1-10 In certain embodiments of Formula Ib, R 1 is C1-C6 alkyl. In certain embodiments of Formula Ib, R is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, and hexyl. In certain embodiments of Formula Ib, R 1 is methyl.

[0108] In certain embodiments of Formula Ib, R 4 is H.

[0109] In certain embodiments of Formula Ib, R 4is an amine protecting group. In certain embodiments of Formula Ib, the amine protecting group is selected from carbobenzyloxy (Cbz), p-methoxybenzylcarbonyl (Moz or MeOZ), tert-butyloxycarbonyl (Boc), 9-fluorenylmethyloxycarbonyl (FMOC), acetyl (Ac), benzoyl (Bz), benzyl (Bn), carbamate, p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), succinimide (i.e., cyclic imide), and tosyl (Ts). In certain embodiments of Formula Ib, the amine protecting group is Boc.

[0110] In certain embodiments of Formula Ib, R 4 is -LT.

[0111] In certain embodiments of Formula Ib, n is an integer from 1 to 10. In certain embodiments, n is an integer from 1 to 5. In certain embodiments, n is 1, 2, 3, 4, or 5. In certain embodiments, n is 2.

[0112] In certain embodiments of Formula Ib, R 1 is H and C 1-10 alkyl, and R 4 is H and n is an integer from 1 to 20. In certain embodiments of Formula Ib, R 1 is H and C 1-10 alkyl, and R 4 is H and n is an integer from 1 to 10. In certain embodiments of Formula Ib, R 1 is H and C 1-10 alkyl, and R 4 is H and n is an integer from 1 to 5. In certain embodiments of Formula Ib, R 1 is H and C 1-10 alkyl, and R 4 is H and n is 2.

[0113] In certain embodiments of Formula Ib, R 1 is H and C 1-10 alkyl, and R 4is an amine protecting group and n is an integer from 1 to 20. In certain embodiments of Formula Ib, R 1 is H and C 1-10 alkyl, and R 4 is an amine protecting group and n is an integer from 1 to 10. In certain embodiments of Formula Ib, R 1 is H and C 1-10 alkyl, and R 4 is an amine protecting group and n is an integer from 1 to 5. In certain embodiments of Formula Ib, R 1 is H and C 1-10 alkyl, and R 4 is an amine protecting group and n is 2.

[0114] In certain embodiments of Formula Ib, R 1 is H and C 1-10 alkyl, and R 4 is -LT and n is an integer from 1 to 20. In certain embodiments of Formula Ib, R 1 is H and C 1-10 alkyl, and R 4 is -LT and n is an integer from 1 to 10. In certain embodiments of Formula Ib, R 1 is H and C 1-10 alkyl, and R 4 is -LT and n is an integer from 1 to 5. In certain embodiments of Formula Ib, R 1 is H and C 1-10 alkyl, and R 4 is -LT and n is 2.

[0115] In certain embodiments, the compound of formula I-Ib is selected from: [Table 1] or a pharmaceutically acceptable salt thereof.

[0116] In certain embodiments of Formula I-Ib, the pharmaceutically acceptable salt is an inorganic or organic acid salt of the compound of Formula I-Ib. In certain embodiments of Formula I-Ib, the pharmaceutically acceptable salt is an organic acid salt, for example, a salt of an organic acid such as acetic acid, trifluoroacetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid. In certain embodiments of Formula I-Ib, the pharmaceutically acceptable salt is trifluoroacetic acid (TFA).

[0117] In certain embodiments of Formulas I-Ib, as described above, R 4 is -LT, L is a bond or a bivalent linker, and T comprises (a) a chelating moiety suitable for chelating a radionuclide, (b) an imaging agent, or (c) a drug. In certain embodiments of Formula I-Ib, T is a means for chelating a radionuclide.

[0118] In certain embodiments of Formulas I-Ib, R 4 is -LT, where L is a bond such that the terminal nitrogen of the compound of formula I is directly attached to T.

[0119] In certain embodiments of Formula I, R 4 is -LT, and L is a bivalent linker linked, connected, or bonded to T. In certain embodiments of Formula I-Ib, L is a cleavable bivalent linker. Cleavable linkers include linkers that are cleaved by intracellular metabolism after internalization (e.g., cleavage by hydrolysis, reduction, or enzymatic reaction). In certain embodiments of Formula I-Ib, L is a non-cleavable bivalent linker. Non-cleavable linkers include linkers that release the attached payload via lysosomal degradation after internalization.

[0120] In certain embodiments of Formula I-Ib, L is selected from an acid labile linker, a hydrolytically labile linker, an enzymatically cleavable linker, a reduction labile linker, a self-immolative linker, and a non-cleavable linker.

[0121] In certain embodiments of Formula I-Ib, L comprises one or more peptides, amino acids, glucuronides, succinimide thioethers, polyethylene glycol (PEG) units, hydrazones, mal-caproyl units, dipeptide units, valine-citrulline units, para-aminobenzyl (PAB) units, or combinations thereof.

[0122] In certain embodiments of Formula I-Ib, L comprises one or more amino acids. Suitable amino acids include natural, non-natural, standard, non-standard, proteinogenic, non-proteinogenic, and L- or D-α-amino acids. In certain embodiments, the L linker comprises alanine, valine, glycine, leucine, isoleucine, methionine, tryptophan, phenylalanine, proline, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartic acid, glutamic acid, lysine, arginine, histidine, or citrulline, or derivatives thereof. In some embodiments, L comprises 2, 3, 4, 5, or 6 amino acids.

[0123] In certain embodiments of Formulas I-Ib, R 4is -LT, and T comprises a chelating moiety suitable for chelating a radionuclide. In certain embodiments of Formula I-Ib, the chelating moiety comprises 2 to 8 binding moieties. In certain embodiments of Formula I-Ib, the chelating moiety is selected from the group consisting of DOTAGA (1,4,7,10-tetraazacyclododecane, 1-(glutaric acid)-4,7,10-triacetic acid), DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid), DOTASA (1,4,7,10-tetraazacyclododecane-1-(2-succinic acid)-4,7,10-triacetic acid), CB-DO2A (10-bis(carbo hydroxymethyl)-1,4,7,10-tetraazabicyclo[5.5.2]tetradecane), DEPA (7-[2-(bis-carboxymethylamino)-ethyl]-4,10-bis-carboxymethyl-1,4,7,10-tetraaza-cyclododec-1-yl-acetic acid)), 3p-C-DEPA (2-[(carboxymethyl)][5-(4-nitrophenyl-1-[4,7,10-tris(carboxymethyl)-1,4, 7,10-tetraazacyclododecan-1-yl]pentan-2-yl)amino]acetic acid), TCMC (2-(4-isothiocyanotobenzyl)-1,4,7,10-tetraaza-1,4,7,10-tetra-(2-carbamonylmethyl)-cyclododecane), oxo-DO3A (1-oxa-4,7,10-triazacyclododecane-5-S-(4-isothiocyanatobenzyl)-4,7,10-triacetic acid), p-N H2-Bn-oxo-DO3A (1-oxa-4,7,10-tetraazacyclododecane-5-S-(4-aminobenzyl)-4,7,10-triacetic acid), TE2A ((1,8-N,N'-bis-(carboxymethyl)-1,4,8,11-tetraazacyclotetradecane), MM-TE2A, DM-TE2A, CB-TE2A (4,11-bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane), CB-TE1A1P (4,8,11-tetraazacyclotetradecane-1-(methanephosphonic acid)-8-(methanecarboxylic acid), CB-TE2P (1,4,8,11-tetraazacyclotetradecane-1,8-bis(methanephosphonic acid), TETA (1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid), NOTA (1,4,7-triazacyclononane-N,N',N"-triacetic acid), NODA (1,4,7-triazacyclononane-N,N',N"-triacetic acid), nan-1,4-diacetate), NODAGA (1,4,7-triazacyclononane-1-glutaric-4,7-acetic acid) (also known as NOTAGA), NODA desferoxamine (1,4,7-triazacyclononane-1,4-diyl)diacetic acid DFO), NETA ([4-[2-(bis-carboxymethylamino)-ethyl]-7-carboxymethyl-[1,4,7]triazonan-1-yl}acetic acid), TACN-TM (N,N',N",Tris(2-mercapto) ethyl)-1,4,7-triazacyclononane), Diamsar (1,8-diamino-3,6,10,13,16,19-hexazabicyclo(6,6,6)eicosane, 3,6,10,13,16,19-hexazabicyclo[6.6.6]eicosane-1,8-diamine), Sarar (1-N-(4-aminobenzyl)-3,6,10,13,16,19-hexazabicyclo[6.6.6]eicosane-1,8-diamine), AmBaSar (4-((8-amino- In certain embodiments of Formula I-Ib, the chelating moiety is selected from DOTAGA, DOTA, NOTA, NODAGA, and NODA.

[0124] In certain embodiments of Formula I-Ib, the chelating moiety is NODAGA. In certain embodiments of Formula I-Ib, R 4 In certain embodiments of Formula I-Ib, R4 is -LT, L is a bond, and R 4 is NODAGA.

[0125] In certain embodiments of Formulas I-Ib, T comprises a chelating moiety that does not contain a radionuclide.

[0126] In certain embodiments, the compound of formula I-Ib is selected from: [Table 2] or a pharmaceutically acceptable salt thereof.

[0127] In certain embodiments of Formula I-Ib, T comprises a chelating moiety chelated to a radionuclide. In certain embodiments of Formula I-Ib, the radionuclide is selected from alpha-emitting isotopes, beta-emitting isotopes, gamma-emitting isotopes, Auger electron-emitting isotopes, X-ray-emitting isotopes, and fluorescent-emitting isotopes. In certain embodiments of Formula I-Ib, the radionuclide is 225 Ac, 51 Cr, 66 Ga, 67 Ga, 68 Ga, [ 18 F]AlF, 111 In, 113m In, 52m Mn, 99m Tc, 186 Re, 188 Re, 139 La, 140 La, 175 Yb, 179 Yb, 153 Sm, 177m Sn, 166 Ho, 86 Y, 88 Y, 90 Y, 149 Pm, 165 Dy, 169 Er, 177 Lu, 52 Fe, 43 Sc, 44 Sc, 46 Sc,47 Sc, 142 Pr, 157 Gd, 159 Gd, 212 Bi, 213 Bi, 72 As, 77 As, 97 Ru, 109 Pd, 105 Rh, 101m Rh, 119 Sb, 197 Hg, 151 EU, 153 EU, 169 EU, 201 Tl, 149 Tb, 152 Tb, 155 Tb, 161 Tb, 203 Pb, 212 Pb, 151 Pm, 153 Pm, 142 Pr, 143 Pr, 55 Co, 60 Cu, 61 Cu, 62 Cu, 64 Cu, 67 Cu, 62 Zn, 188 Re, 198 Au, 199 Au, 227 Th, 111 Ag, 199 Ag, 211 At, 223 Ra, 88 Zr and 89 Zr.

[0128] In certain embodiments of Formulas I-Ib, the radionuclide is 61 Cu, 62 Cu, 64 Cu and 67 In certain embodiments of Formulas I-Ib, the radionuclide is selected from Cu. 61 In certain embodiments of Formulas I-Ib, the radionuclide is Cu. 67 It is Cu.

[0129] In certain embodiments of Formulas I-Ib, R4 is -L-NODAGA-*Cu, and *Cu is 61 Cu, 62 Cu, 64 Cu and 67 In certain embodiments of Formulas I-Ib, R 4 is -LT, L is a bond, and R 4 is NODAGA-*Cu, and *Cu is 61 Cu, 62 Cu, 64 Cu and 67 Cu.

[0130] In certain embodiments of Formulas I-Ib, R 1 is selected from H and methyl; R 4 is -LT, T comprises a chelating moiety chelated to a radionuclide, and the radionuclide is 61 Cu, 64 Cu and 67 Cu; n is an integer from 1 to 5.

[0131] In certain embodiments of Formulas I-Ib, R 1 is selected from H and methyl; R 4 is -LT, T comprises a chelating moiety chelated to a radionuclide, and the radionuclide is 61 Cu; and n is an integer from 1 to 5.

[0132] In certain embodiments of Formulas I-Ib, R 1 is selected from H and methyl; R 4 is -LT, T comprises a chelating moiety chelated to a radionuclide, and the radionuclide is 64 Cu; and n is an integer from 1 to 5.

[0133] In certain embodiments of Formulas I-Ib, R 1 is selected from H and methyl; R 4 is -LT, T comprises a chelating moiety chelated to a radionuclide, and the radionuclide is 67 Cu; and n is an integer from 1 to 5.

[0134] In certain embodiments of Formulas I-Ib, R 1 is selected from H and methyl; R 4 is -LT, wherein T comprises a chelating moiety chelated to a radionuclide, the chelating moiety being selected from DOTAGA, DOTA, NOTA, NODAGA, and NODA; and n is an integer from 1 to 5.

[0135] In certain embodiments of Formulas I-Ib, R 1 is selected from H and methyl; R 4 is -LT, T comprises a chelating moiety chelated to a radionuclide, the chelating moiety being DOTAGA; and n is an integer from 1 to 5.

[0136] In certain embodiments of Formulas I-Ib, R 1 is selected from H and methyl; R 4 is -LT, T comprises a chelating moiety chelated to a radionuclide, the chelating moiety being DOTA; and n is an integer from 1 to 5.

[0137] In certain embodiments of Formulas I-Ib, R 1 is selected from H and methyl; R 4 is -LT, T comprises a chelating moiety chelated to a radionuclide, the chelating moiety is NOTA; and n is an integer from 1 to 5.

[0138] In certain embodiments of Formulas I-Ib, R 1 is selected from H and methyl; R 4 is -LT, T comprises a chelating moiety chelated to a radionuclide, the chelating moiety being NODAGA; and n is an integer from 1 to 5.

[0139] In certain embodiments of Formulas I-Ib, R 1 is selected from H and methyl; R 4is -LT, T comprises a chelating moiety chelated to a radionuclide, the chelating moiety being NODA; and n is an integer from 1 to 5.

[0140] In certain embodiments of Formulas I-Ib, R 1 is selected from H and methyl; R 4 is -LT, T comprises a chelating moiety chelated to a radionuclide, the chelating moiety being selected from DOTAGA, DOTA, NOTA, NODAGA, and NODA; the radionuclide is 61 Cu, 64 Cu and 67 Cu; n is an integer from 1 to 5.

[0141] In certain embodiments of Formulas I-Ib, R 1 is selected from H and methyl; R 4 is -LT, T comprises a chelating moiety chelated to a radionuclide, the chelating moiety is DOTAGA, and the radionuclide is 61 Cu, 64 Cu and 67 Cu; n is an integer from 1 to 5.

[0142] In certain embodiments of Formulas I-Ib, R 1 is selected from H and methyl; R 4 is -LT, T comprises a chelating moiety chelated to a radionuclide, the chelating moiety is DOTAGA, and the radionuclide is 61 Cu; and n is an integer from 1 to 5.

[0143] In certain embodiments of Formulas I-Ib, R 1 is selected from H and methyl; R 4 is -LT, T comprises a chelating moiety chelated to a radionuclide, the chelating moiety is DOTAGA, and the radionuclide is 64 Cu; and n is an integer from 1 to 5.

[0144] In certain embodiments of Formulas I-Ib, R 1is selected from H and methyl; R 4 is -LT, T comprises a chelating moiety chelated to a radionuclide, the chelating moiety is DOTAGA, and the radionuclide is 67 Cu; and n is an integer from 1 to 5.

[0145] In certain embodiments of Formulas I-Ib, R 1 is selected from H and methyl; R 4 is -LT, T comprises a chelating moiety chelated to a radionuclide, the chelating moiety is DOTA, and the radionuclide is 61 Cu, 64 Cu and 67 Cu; n is an integer from 1 to 5.

[0146] In certain embodiments of Formulas I-Ib, R 1 is selected from H and methyl; R 4 is -LT, T comprises a chelating moiety chelated to a radionuclide, the chelating moiety is DOTA, and the radionuclide is 61 Cu; and n is an integer from 1 to 5.

[0147] In certain embodiments of Formulas I-Ib, R 1 is selected from H and methyl; R 4 is -LT, T comprises a chelating moiety chelated to a radionuclide, the chelating moiety is DOTA, and the radionuclide is 64 Cu; and n is an integer from 1 to 5.

[0148] In certain embodiments of Formulas I-Ib, R 1 is selected from H and methyl; R 4 is -LT, T comprises a chelating moiety chelated to a radionuclide, the chelating moiety is DOTA, and the radionuclide is 67 Cu; and n is an integer from 1 to 5.

[0149] In certain embodiments of Formulas I-Ib, R 1 is selected from H and methyl; R4 is -LT, T comprises a chelating moiety chelated to a radionuclide, the chelating moiety is NOTA, and the radionuclide is 61 Cu, 64 Cu and 67 Cu; n is an integer from 1 to 5.

[0150] In certain embodiments of Formulas I-Ib, R 1 is selected from H and methyl; R 4 is -LT, T comprises a chelating moiety chelated to a radionuclide, the chelating moiety is NOTA, and the radionuclide is 61 Cu; and n is an integer from 1 to 5.

[0151] In certain embodiments of Formulas I-Ib, R 1 is selected from H and methyl; R 4 is -LT, T comprises a chelating moiety chelated to a radionuclide, the chelating moiety is NOTA, and the radionuclide is 64 Cu; and n is an integer from 1 to 5.

[0152] In certain embodiments of Formulas I-Ib, R 1 is selected from H and methyl; R 4 is -LT, T comprises a chelating moiety chelated to a radionuclide, the chelating moiety is NOTA, and the radionuclide is 67 Cu; and n is an integer from 1 to 5.

[0153] In certain embodiments of Formulas I-Ib, R 1 is selected from H and methyl; R 4 is -LT, T comprises a chelating moiety chelated to a radionuclide, the chelating moiety is NODAGA, and the radionuclide is 61 Cu, 64 Cu and 67 Cu; n is an integer from 1 to 5.

[0154] In certain embodiments of Formulas I-Ib, R 1is selected from H and methyl; R 4 is -LT, T comprises a chelating moiety chelated to a radionuclide, the chelating moiety is NODAGA, and the radionuclide is 61 Cu; and n is an integer from 1 to 5.

[0155] In certain embodiments of Formulas I-Ib, R 1 is selected from H and methyl; R 4 is -LT, T comprises a chelating moiety chelated to a radionuclide, the chelating moiety is NODAGA, and the radionuclide is 64 Cu; and n is an integer from 1 to 5.

[0156] In certain embodiments of Formulas I-Ib, R 1 is selected from H and methyl; R 4 is -LT, T comprises a chelating moiety chelated to a radionuclide, the chelating moiety is NODAGA, and the radionuclide is 67 Cu; and n is an integer from 1 to 5.

[0157] In certain embodiments of Formulas I-Ib, R 1 is selected from H and methyl; R 4 is -LT, T comprises a chelating moiety chelated to a radionuclide, the chelating moiety is NODA, and the radionuclide is 61 Cu, 64 Cu and 67 Cu; n is an integer from 1 to 5.

[0158] In certain embodiments of Formulas I-Ib, R 1 is selected from H and methyl; R 4 is -LT, T comprises a chelating moiety chelated to a radionuclide, the chelating moiety is NODA, and the radionuclide is 61 Cu; and n is an integer from 1 to 5.

[0159] In certain embodiments of Formulas I-Ib, R 1is selected from H and methyl; R 4 is -LT, T comprises a chelating moiety chelated to a radionuclide, the chelating moiety is NODA, and the radionuclide is 64 Cu; and n is an integer from 1 to 5.

[0160] In certain embodiments of Formulas I-Ib, R 1 is selected from H and methyl; R 4 is -LT, T comprises a chelating moiety chelated to a radionuclide, the chelating moiety is NODA, and the radionuclide is 67 Cu; and n is an integer from 1 to 5.

[0161] In certain embodiments, the compound of formula I-Ib is: [Table 3-1] [Table 3-2] or a pharmaceutically acceptable salt thereof, and *Cu is 61 Cu, 62 Cu, 64 Cu and 67 From Cu, especially 61 Cu and 67 Cu.

[0162] In certain embodiments of Formula I-Ib, T comprises an imaging agent. In certain embodiments of Formula I-Ib, the imaging agent comprises a radionuclide. In certain embodiments of Formula I-Ib, the radionuclide is 18 F, 14 C. 11 C. 13 N, 32 P, 35 S, 125 I, 131 I, 124 I, 123 I and 15 O is selected.

[0163] In certain embodiments of Formula I-Ib, the imaging agent comprises a non-chelated radioactive moiety. In certain embodiments of Formula I-Ib, the non-chelated radioactive moiety is 11 C]Cu-methionine (Met), [ 18 F]F-2-fluoro-2-deoxyglucose (FDG), [ 18 F]F labeled C6- 10 aryl, and [ 18 F]F label C 5-9 heteroaryl.

[0164] In certain embodiments of Formula I-Ib, the imaging agent comprises a chelating moiety chelated to a radionuclide. In certain embodiments of Formula I-Ib, the chelating moiety comprises 2 to 8 binding moieties. In certain embodiments of Formula I-Ib, the chelating moiety is selected from the group consisting of DOTAGA (1,4,7,10-tetraazacyclododecane, 1-(glutaric acid)-4,7,10-triacetic acid), DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid), DOTASA (1,4,7,10-tetraazacyclododecane-1-(2-succinic acid)-4,7,10-triacetic acid), CB-DO2A (10-bis(carbo hydroxymethyl)-1,4,7,10-tetraazabicyclo[5.5.2]tetradecane), DEPA (7-[2-(bis-carboxymethylamino)-ethyl]-4,10-bis-carboxymethyl-1,4,7,10-tetraaza-cyclododec-1-yl-acetic acid)), 3p-C-DEPA (2-[(carboxymethyl)][5-(4-nitrophenyl-1-[4,7,10-tris(carboxymethyl)-1,4, 7,10-tetraazacyclododecan-1-yl]pentan-2-yl)amino]acetic acid), TCMC (2-(4-isothiocyanotobenzyl)-1,4,7,10-tetraaza-1,4,7,10-tetra-(2-carbamonylmethyl)-cyclododecane), oxo-DO3A (1-oxa-4,7,10-triazacyclododecane-5-S-(4-isothiocyanatobenzyl)-4,7,10-triacetic acid), p-N H2-Bn-oxo-DO3A (1-oxa-4,7,10-tetraazacyclododecane-5-S-(4-aminobenzyl)-4,7,10-triacetic acid), TE2A ((1,8-N,N'-bis-(carboxymethyl)-1,4,8,11-tetraazacyclotetradecane), MM-TE2A, DM-TE2A, CB-TE2A (4,11-bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane), CB-TE1A1P (4,8,11-tetraazacyclotetradecane-1-(methanephosphonic acid)-8-(methanecarboxylic acid), CB-TE2P (1,4,8,11-tetraazacyclotetradecane-1,8-bis(methanephosphonic acid), TETA (1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid), NOTA (1,4,7-triazacyclononane-N,N',N"-triacetic acid), NODA (1,4,7-triazacyclononane-1,4-diazomethane) acetate), NODAGA (1,4,7-triazacyclononane-1-glutaric-4,7-acetic acid) (also known as NOTAGA), NODA desferoxamine (1,4,7-triazacyclononane-1,4-diyl)diacetic acid (DFO), NETA ([4-[2-(bis-carboxymethylamino)-ethyl]-7-carboxymethyl-[1,4,7]triazonan-1-yl}acetic acid), TACN-TM (N,N',N”,tris(2-mercaptoethyl)-1,4,7-triazacyclononane-1,4-diacetate), nonane), Diamsar (1,8-diamino-3,6,10,13,16,19-hexazabicyclo(6,6,6)eicosane, 3,6,10,13,16,19-hexazabicyclo[6.6.6]eicosane-1,8-diamine), Sarar (1-N-(4-aminobenzyl)-3,6,10,13,16,19-hexazabicyclo[6.6.6]eicosane-1,8-diamine), AmBaSar (4-((8-amino-3,6,10,13,16,19-hexazabicyclo[6 In certain embodiments of Formula I-Ib, the chelating moiety is selected from DOTAGA, DOTA, NOTA, NODAGA, and NODA. In some embodiments of Formula I-Ib, the chelating moiety is NODAGA.

[0165] In certain embodiments of Formula I-Ib, the radionuclide chelated to the chelating moiety of the imaging agent is selected from alpha-emitting isotopes, beta-emitting isotopes, gamma-emitting isotopes, Auger electron-emitting isotopes, X-ray-emitting isotopes, and fluorescent-emitting isotopes. 225 Ac, 51 Cr, 66 Ga, 67 Ga, 68 Ga, [ 18 F]AlF, 111 In, 113m In, 52m Mn, 99m Tc, 186 Re, 188 Re, 139 La, 140 La, 175 Yb, 179 Yb, 153 Sm, 177m Sn, 166 Ho, 86 Y, 88 Y, 90 Y, 149 Pm, 165 Dy, 169 Er, 177 Lu, 52 Fe, 43 Sc, 44 Sc, 46 Sc, 47 Sc, 142 Pr, 157 Gd, 159 Gd, 212 Bi, 213 Bi, 72 As, 77 As, 97 Ru, 109 Pd, 105 Rh, 101m Rh, 119 Sb, 197 Hg, 151 EU, 153 EU, 169 EU, 201 Tl, 149 Tb, 152 Tb, 155 Tb, 161 Tb, 203 Pb, 212 Pb,151 Pm, 153 Pm, 142 Pr, 143 Pr, 55 Co, 60 Cu, 61 Cu, 62 Cu, 64 Cu, 67 Cu, 62 Zn, 188 Re, 198 Au, 199 Au, 227 Th, 111 Ag, 199 Ag, 211 At, 223 Ra, 88 Zr and 89 In certain embodiments of Formulas I-Ib, the radionuclide chelated within the chelating moiety of the imaging agent is selected from Zr. 61 It is Cu.

[0166] In certain embodiments of Formula I-Ib, T comprises an imaging agent comprising a chelating moiety chelated to a radionuclide. In certain embodiments of Formula I-Ib, T comprises NODAGA ( 61 Cu-NODAGA) chelated 61 In certain embodiments of Formulas I-Ib, T includes NODAGA( 61 Cu-NODAGA) chelated 61 is.

[0167] In certain embodiments of Formulas I-Ib, the imaging agent is a fluorescent dye, hi certain embodiments, the fluorescent dye is selected from one of the following classes: xanthene, acridine, oxazine, cyanine, styryl dye, coumarin, porphine, metal-ligand-complex, fluorescent protein, nanocrystal, perylene, boron-dipyrromethene, and phthalocyanine.

[0168] In certain embodiments of Formulas I-Ib, T comprises a drug.

[0169] In certain embodiments of Formula I-Ib, the drug comprises a chelating moiety chelated to a radionuclide. In certain embodiments, the chelating moiety comprises 2 to 8 binding moieties. In certain embodiments, the chelating moiety is selected from the group consisting of DOTAGA (1,4,7,10-tetraazacyclododecane, 1-(glutaric acid)-4,7,10-triacetic acid), DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid), DOTASA (1,4,7,10-tetraazacyclododecane-1-(2-succinic acid)-4,7,10-triacetic acid), CB-DO2A (10-bis(carboxymethyl) DEPA (7-[2-(bis-carboxymethylamino)-ethyl]-4,10-bis-carboxymethyl-1,4,7,10-tetraaza-cyclododec-1-yl-acetic acid)), 3p-C-DEPA (2-[(carboxymethyl)][5-(4-nitrophenyl-1-[4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazabicyclo[5.5.2]tetradecane]), ... 0-tetraazacyclododecan-1-yl]pentan-2-yl)amino]acetic acid), TCMC (2-(4-isothiocyanotobenzyl)-1,4,7,10-tetraaza-1,4,7,10-tetra-(2-carbamonylmethyl)-cyclododecane), oxo-DO3A (1-oxa-4,7,10-triazacyclododecane-5-S-(4-isothiocyanatobenzyl)-4,7,10-triacetic acid), p-NH2 -Bn-oxo-DO3A (1-oxa-4,7,10-tetraazacyclododecane-5-S-(4-aminobenzyl)-4,7,10-triacetic acid), TE2A ((1,8-N,N'-bis-(carboxymethyl)-1,4,8,11-tetraazacyclotetradecane), MM-TE2A, DM-TE2A, CB-TE2A (4,11-bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane), CB-TE1A1P (4,8,11-tetraazacyclotetradecane-1-(methanephosphonic acid)-8-(methanecarboxylic acid), CB-TE2P (1,4,8,11-tetraazacyclotetradecane-1,8-bis(methanephosphonic acid), TETA (1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid), NOTA (1,4,7-triazacyclononane-N,N',N"-triacetic acid), NODA (1,4,7-triazacyclononane-1, 4-diacetate), NODAGA (1,4,7-triazacyclononane-1-glutaric-4,7-acetic acid) (also known as NOTAGA), NODA desferoxamine (1,4,7-triazacyclononane-1,4-diyl)diacetic acid DFO), NETA ([4-[2-(bis-carboxymethylamino)-ethyl]-7-carboxymethyl-[1,4,7]triazonan-1-yl}acetic acid), TACN-TM (N,N',N”,tris(2-mercaptoethyl)-1,4,7- triazacyclononane), Diamsar (1,8-diamino-3,6,10,13,16,19-hexazabicyclo(6,6,6)eicosane, 3,6,10,13,16,19-hexazabicyclo[6.6.6]eicosane-1,8-diamine), Sarar (1-N-(4-aminobenzyl)-3,6,10,13,16,19-hexazabicyclo[6.6.6]eicosane-1,8-diamine), AmBaSar (4-((8-amino-3,6,10,13,16,19-hexazabicyclo[6.6.6]eicosane-1,8-diamine), In certain embodiments, the chelating moiety is selected from 4,4'-((3,6,10,13,16,19-hexaazabicyclo[6.6.6]icosan-1-ylamino)methyl)benzoic acid) and 4,4'-((3,6,10,13,16,19-hexaazabicyclo[6.6.6]ico-san-1,8-diylbis(aza-nediyl))bis(methylene))dibenzoic acid (BaBaSar). In certain embodiments, the chelating moiety is selected from DOTAGA, DOTA, NOTA, NODAGA, and NODA. In certain embodiments, the chelating moiety is NODAGA.

[0170] In certain embodiments of Formula I-Ib, the radionuclide chelated to the chelating moiety of the drug is selected from alpha-emitting isotopes and beta-emitting isotopes. In certain embodiments of Formula I-Ib, the radionuclide chelated to the chelating moiety of the drug is an alpha-emitting isotope. In certain embodiments of Formula I-Ib, the radionuclide chelated to the chelating moiety of the drug is 225 Ac, 51 Cr, 66 Ga, 67 Ga, 68 Ga, [ 18 F]AlF, 111 In, 113m In, 52m Mn, 99m Tc, 186 Re, 188 Re, 139 La, 140 La, 175 Yb, 179 Yb, 153 Sm, 177m Sn, 166 Ho, 86 Y, 88 Y, 90 Y, 149 Pm, 165 Dy, 169 Er, 177 Lu, 52 Fe, 43 Sc, 44 Sc, 46 Sc, 47 Sc, 142 Pr, 157 Gd, 159 Gd, 212 Bi, 213 Bi, 72 As, 77 As, 97 Ru, 109 Pd, 105 Rh, 101m Rh, 119 Sb, 197 Hg, 151 EU, 153 EU, 169 EU, 201 Tl, 149 Tb, 152 Tb, 155 Tb, 161 Tb,203 Pb, 212 Pb, 151 Pm, 153 Pm, 142 Pr, 143 Pr, 55 Co, 60 Cu, 61 Cu, 62 Cu, 64 Cu, 67 Cu, 62 Zn, 188 Re, 198 Au, 199 Au, 227 Th, 111 Ag, 199 Ag, 211 At, 223 Ra, 88 Zr and 89 In certain embodiments of Formulas I-Ib, the radionuclide chelated to the chelating moiety of the drug is selected from Zr. 67 It is Cu.

[0171] In certain embodiments of Formula I-Ib, T comprises a drug comprising a chelating moiety chelated to a radionuclide. In certain embodiments of Formula I-Ib, T comprises NODAGA ([ 67 Cu]Cu-NODAGA) 67 In certain embodiments of Formulas I-Ib, T includes NODAGA([ 67 Cu]Cu-NODAGA) 67 It is Cu.

[0172] In certain embodiments of Formula I-Ib, the drug is a cytotoxic agent. In certain embodiments of Formula I-Ib, the cytotoxic agent is adrenocorticoids and corticosteroids, alkylating agents, antiandrogens, antiestrogens, androgens, aclamycin and aclamycin derivatives, estrogens, antimetabolites such as cytosine arabinoside, purine analogs, pyrimidine analogs, methotrexate, busulfan, carboplatin, chlorambucil, cisplatin and other platinum compounds, taxanes such as tamoxifen, taxol, paclitaxel, paclitaxel, Clitaxel derivatives, Taxoteret® and the like, maytansine and its analogues and derivatives, cyclophosphamide, daunomycin, doxorubicin, rhizoxin, T2 toxin, plant alkaloids, prednisone, hydroxyurea, teniposide, mitomycin, discodermolide, microtubule inhibitors, epothilones, tubulysins, cyclopropylbenz[e]indolone, seco-cyclopropylbenz[e]indolone, O-Ac-seco-cyclopropylbenz[e]indolone , bleomycin and any other antibiotics, nitrogen mustard, nitrosurea, vincristine, vinblastine, and analogs and derivatives thereof, such as deacetylvinblastine monohydrazide, colchicine, colchicine derivatives, allocolchicine, thiocolchicine, trityl cysteine, halichondrin B, dolastatins such as dolastatin 10, amanitin, such as α-amanitin, camptothecin, irinotecan, and other camptothecin derivatives thereof, geldanamycin, isin and geldanamycin derivatives, estramustine, nocodazole, MAP4, colcemid, inflammatory and pro-inflammatory agents, peptide and peptidomimetic signal transduction inhibitors, penicillins, cephalosporins, vancomycin, erythromycin, clindamycin, rifampin, chloramphenicol, aminoglycoside antibiotics, gentamicin, amphotericin B, acyclovir, trifluridine, ganciclovir, zidovudine, amantadine, and ribavirin.

[0173] In certain embodiments of Formulas I-Ib, the drug is a peptide, an oligopeptide, a retro-inverso oligopeptide, a protein, a protein analog in which at least one non-peptide bond replaces a peptide bond, an apoprotein, a glycoprotein, an enzyme, a coenzyme, an enzyme inhibitor, an amino acid and its derivatives, a receptor and other membrane proteins; an antigen and its antibodies; a hapten and its antibodies; a hormone, a lipid, a phospholipid, a liposome; a toxin; an antibiotic; an analgesic; a bronchodilator; a beta-blocker; an antibacterial; an antihypertensive; an anti-inflammator Selected from cardiovascular agents, including arrhythmias, cardiac glycosides, antianginals, and vasodilators; central nervous system acting agents, including stimulants, psychotropics, antimanics, and depressants; antivirals; antihistamines; cancer drugs, including chemotherapeutic agents; tranquilizers; antidepressants; H-2 antagonists; anticonvulsants; antiemetics; prostaglandins and prostaglandin analogs; muscle relaxants; anti-inflammatory substances; stimulants; decongestants; antiemetics; diuretics; antispasmodics; antiasthmatics; antiparkinsonian agents; expectorants; cough suppressants; mucolytics; and minerals and nutritional additives.

[0174] The present disclosure also provides additional compounds, including when the compound is a compound of Formula II: [ka] R 3 is H, C 1-10 Alkyl, C 2-10 Alkenyl, C 3-10 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, C 2-9 Heterocyclyl, or C 5-9 heteroaryl, optionally substituted with one or more substituents selected from —OH, —OR′, ═O, ═S, —SH, —SR′, —NH, —NHR′, —N(R′) , —NHCOR′, —NR′COR′, halogen, —CN, —COH, —COR′, —CHO, —COR′, —CONH, —CONHR′, —CON(R′) , —NO , —OP(O)(OH) , —SOH, —SOR′, —SOR′, and —SOR′; R′ is independently for each occurrence C1-10 Alkyl or C 3-10 is cycloalkyl; or R 3 together with the L moiety, form a bond between the nitrogen atom and C 2-9 Forming a heterocyclic ring; L is a bivalent linker, preferably up to 20 atoms in length; or a pharmaceutically acceptable salt thereof.

[0175] In certain embodiments of Formula II, R 3 is H. In certain embodiments of Formula II, R 3 is C1-C 10 In certain embodiments of Formula II, R 3 is C1-C6 alkyl. In certain embodiments of Formula II, R 3 is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, and hexyl. In certain embodiments of Formula II, R 3 is methyl.

[0176] In certain embodiments of Formula II, L is a bivalent linker as described above for Formula I.

[0177] In certain embodiments of Formula II, L is up to 20 atoms long (meaning that up to 20 atoms are consecutively linked to form the backbone of L extending from each of the two binding sites of L to the remainder of the compound). In certain embodiments of Formula II, L is up to 15 atoms long. In certain embodiments of Formula II, L is up to 10 atoms long. In certain embodiments of Formula II, L is up to 5 atoms long.

[0178] In certain embodiments of Formula II, L is —N(R 2 )-, -O-, -S-, -C(=NR 2 )-, -C(=O)-, C 1-10 Alkylene, C 2-10 Alkenylene, C 3-10 Alkynylene, C 4-10 Cycloalkylene, C 6-10arylene, and combinations thereof; R 2 independently for each occurrence, H, C 1-10 Alkyl, C 2-10 Alkenyl, C 3-10 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, C 2-9 Heterocyclyl, or C 5-9 heteroaryl, optionally substituted with one or more substituents selected from —OH, —OR′, ═O, ═S, —SH, —SR′, —NH, —NHR′, —N(R′) , —NHCOR′, NR′COR′, halogen, —CN, —COH, —COR′, —CHO, —COR′, —CONH, —CONHR′, —CON(R′) , —NO , —OP(O)(OH) , —SOH, —SOR′, —SOR′, and —SOR′, wherein R′ is independently for each occurrence C 1-10 Alkyl or C 3-10 It is cycloalkyl.

[0179] In certain embodiments of Formula II, L is one or more —N(R 2 )-group, and R 2 is independently for each occurrence H or C 1-10 Alkyl, for example methyl.

[0180] In certain embodiments of Formula II, L contains one or more -C(=O)- groups.

[0181] In certain embodiments of Formula II, L is one or more C 1-10 Contains an alkylene group.

[0182] In certain embodiments of Formula II, L is one or more —N(R 2 In certain embodiments of Formula II, L includes one or more -N(R 2 )-group and one or more C 1-10 In certain embodiments of Formula II, L comprises one or more -C(=O)- groups and one or more C 1-10In certain embodiments of Formula II, L comprises one or more —N(R 2 )- group, one or more -C(=O)- groups, and one or more C 1-10 Contains an alkylene group.

[0183] In certain embodiments of Formula II, R 3 together with the L moiety, form a bond between the nitrogen atom and C 2-9 In certain embodiments of Formula II, C 2-9 The heterocycle is a 5-, 6-, or 7-membered heterocycle. In certain embodiments of Formula II, C 2-9 The heterocycle is a 5-membered heterocycle selected from pyrrolidine, pyrazolidine, and imidazoline. In certain embodiments of Formula II, C 2-9 The heterocycle is a 6-membered heterocycle selected from piperazine, hexahydropyrimidine, hexahydropyridazine, 1,2,3-triazinane, 1,2,4-triazinane, and 1,3,5-triazinane. In certain embodiments of Formula II, C 2-9 The heterocycle is piperazine.

[0184] In certain embodiments of Formula II, R 3 is H, L is up to 20 atoms long, -N(R 2 )-, -O-, -S-, -C(=NR 2 )-, -C(=O)-, C 1-10 Alkylene, C 2-10 Alkenylene, C 3-10 Alkynylene, C 4-10 Cycloalkylene, C 6-10 arylene, and combinations thereof; R 2 independently for each occurrence, H, C 1-10 Alkyl, C 2-10 Alkenyl, C 3-10 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, C 2-9 Heterocyclyl, or C 5-9heteroaryl, optionally substituted with one or more substituents selected from —OH, —OR′, ═O, ═S, —SH, —SR′, —NH, —NHR′, —N(R′) , —NHCOR′, NR′COR′, halogen, —CN, —COH, —COR′, —CHO, —COR′, —CONH, —CONHR′, —CON(R′) , —NO , —OP(O)(OH) , —SOH, —SOR′, —SOR′, and —SOR′, wherein R′ is independently for each occurrence C 1-10 Alkyl or C 3-10 In certain embodiments of Formula II, R 3 is H, L is up to 20 atoms long, -N(R 2 )-, -O-, -C(=O)-, C 1-10 alkylene, and combinations thereof; R 2 and / or each occurrence independently represents H and C 1-10 alkyl.

[0185] In certain embodiments of Formula II, R 3 is H, L is up to 20 atoms long, and one or more -N(R 2 )-group, and R 2 is independently for each occurrence H or C 1-10 It is alkyl, preferably methyl.

[0186] In certain embodiments of Formula II, R 3 is H, and L is up to 20 atoms long and contains one or more -C(=O)- groups.

[0187] In certain embodiments of Formula II, R 3 is H, L is up to 20 atoms long, and one or more C 1-10 Contains an alkylene group.

[0188] In certain embodiments of Formula II, R 3 is H, L is up to 20 atoms long, and has one or more C(=O)- groups and one or more C 1-10 In certain embodiments of Formula II, R3 is H, L is up to 20 atoms in length, and has one or more -C(=O)- groups and one or more -N(R 2 )-group, and R 2 is independently for each occurrence H or C 1-10 In certain embodiments of Formula II, R 3 is H, L is up to 20 atoms long, and one or more C 1-10 an alkylene group and one or more -N(R 2 )-group, and R 2 is independently for each occurrence H or C 1-10 In certain embodiments of Formula II, R 3 is H, L is up to 20 atoms long, and has one or more -C(=O)- groups, one or more C 1-10 an alkylene group and one or more -N(R 2 )-group, and R 2 is independently for each occurrence H or C 1-10 It is alkyl, preferably methyl.

[0189] In certain embodiments of Formula II, R 3 together with the L moiety to form the nitrogen atom and C to which they are attached. 2-9 form a heterocyclic ring, L is up to 20 atoms long, -N(R 2 )-, -O-, -S-, -C(=NR 2 )-, -C(=O)-, C 1-10 Alkylene, C 2-10 Alkenylene, C 3-10 Alkynylene, C 4-10 Cycloalkylene, C 6-10 arylene, and combinations thereof; R 2 independently for each occurrence, H, C 1-10 Alkyl, C 2-10 Alkenyl, C 3-10 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, C 2-9 Heterocyclyl, or C 5-9heteroaryl, optionally substituted with one or more substituents selected from —OH, —OR′, ═O, ═S, —SH, —SR′, —NH, —NHR′, —N(R′) , —NHCOR′, NR′COR′, halogen, —CN, —COH, —COR′, —CHO, —COR′, —CONH, —CONHR′, —CON(R′) , —NO , —OP(O)(OH) , —SOH, —SOR′, —SOR′, and —SOR′, wherein R′ is independently for each occurrence C 1-10 Alkyl or C 3-10 It is cycloalkyl.

[0190] In certain embodiments of Formula II, R 3 together with the L moiety to form the nitrogen atom and C to which they are attached. 2-9 form a heterocyclic ring, L is up to 20 atoms long, and N(R 2 )-, -O-, -C(=O)-, C 1-10 alkylene, and combinations thereof; 2 independently for each occurrence, H and C 1-10 alkyl, optionally substituted with one or more substituents selected from —OH, —OR′, ═O, ═S, —SH, —SR′, —NH, —NHR′, —N(R′) , —NHCOR′, NR′COR′, halogen, —CN, —COH, —COR′, —CHO, —COR′, —CONH, —CONHR′, —CON(R′) , —NO , —OP(O)(OH) , —SOH, —SOR′, —SOR′, and —SOR′, wherein R′ is independently for each occurrence C 1-10 Alkyl or C 3-10 It is cycloalkyl.

[0191] In certain embodiments of Formula II, R 3 together with the L moiety, form a bond between the nitrogen atom and C 2-9 form a heterocyclic ring, L is up to 20 atoms in length, and one or more -N(R 2 )-, including the presence of R 2 is, independently for each occurrence, H or C 1-10 It is alkyl.

[0192] In certain embodiments of Formula II, the compound is a compound of Formula IIa: [ka] R 1 is H, C 1-10 Alkyl, C 2-10 Alkenyl, C 3-10 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, C 2-9 Heterocyclyl, or C 5-9 heteroaryl, optionally substituted with one or more substituents selected from —OH, —OR′, ═O, ═S, —SH, —SR′, —NH, —NHR′, —N(R′) , —NHCOR′, —NR′COR′, halogen, —CN, —COH, —COR′, —CHO, —COR′, —CONH, —CONHR′, —CON(R′) , —NO , —OP(O)(OH) , —SOH, —SOR′, —SOR′, and —SOR′; R′ is independently for each occurrence C 1-10 Alkyl or C 3-10 is cycloalkyl, R 3 and L is as described above for Formula II; or a pharmaceutically acceptable salt thereof.

[0193] In certain embodiments of Formula IIa, R 1 is H. In certain embodiments of Formula IIa, R 1 is C1-C 10 In certain embodiments of Formula IIa, R 1 is C1-C6 alkyl. In certain embodiments of Formula IIa, R 1 is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, and hexyl. In certain embodiments of Formula IIa, R 1 is methyl.

[0194] In certain embodiments of Formula IIa, R3 is H. In certain embodiments of Formula IIa, R 3 is C1-C 10 In certain embodiments of Formula IIa, R 3 is C1-C6 alkyl. In certain embodiments of Formula IIa, R 3 is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, and hexyl. In certain embodiments of Formula IIa, R 3 is methyl.

[0195] In certain embodiments of Formula IIa, R 3 together with the L moiety, form a bond between the nitrogen atom and C 2-9 In certain embodiments of Formula IIa, C 2-9 The heterocycle is a 5-, 6-, or 7-membered heterocycle. In certain embodiments of Formula IIa, C 2-9 The heterocycle is a 5-membered heterocycle selected from pyrrolidine, pyrazolidine, and imidazoline. In certain embodiments of Formula IIa, C 2-9 The heterocycle is a 6-membered heterocycle selected from piperazine, hexahydropyrimidine, hexahydropyridazine, 1,2,3-triazinane, 1,2,4-triazinane, and 1,3,5-triazinane. In certain embodiments of Formula IIa, C 2-9 The heterocycle is piperazine.

[0196] In certain embodiments of Formula IIa, L is a bivalent linker as described above for Formula I.

[0197] In certain embodiments of Formula IIa, L is up to 20 atoms in length. In certain embodiments of Formula IIa, L is up to 15 atoms in length. In certain embodiments of Formula IIa, L is up to 10 atoms in length. In certain embodiments of Formula IIa, L is up to 5 atoms in length.

[0198] In certain embodiments of Formula IIa, L is —N(R 2 )-, -O-, -S-, -C(=NR 2 )-, -C(=O)-, C 1-10 Alkylene, C2-10 Alkenylene, C 3-10 Alkynylene, C 4-10 Cycloalkylene, C 6-10 arylene, and combinations thereof; R 2 independently for each occurrence, H, C 1-10 Alkyl, C 2-10 Alkenyl, C 3-10 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, C 2-9 Heterocyclyl, or C 5-9 heteroaryl, optionally substituted with one or more substituents selected from —OH, —OR′, ═O, ═S, —SH, —SR′, —NH, —NHR′, —N(R′) , —NHCOR′, NR′COR′, halogen, —CN, —COH, —COR′, —CHO, —COR′, —CONH, —CONHR′, —CON(R′) , —NO , —OP(O)(OH) , —SOH, —SOR′, —SOR′, and —SOR′, wherein R′ is independently for each occurrence C 1-10 Alkyl or C 3-10 It is cycloalkyl.

[0199] In certain embodiments of Formula IIa, L is one or more —N(R 2 )-, including R 2 is independently for each occurrence H or C 1-10 Alkyl, for example methyl.

[0200] In certain embodiments of Formula IIa, L contains one or more -C(=O)- groups.

[0201] In certain embodiments of Formula IIa, L is one or more C 1-10 Contains an alkylene group.

[0202] In certain embodiments of Formula IIa, L is one or more —N(R 2 In certain embodiments of Formula IIa, L includes one or more -N(R 2 )-group and one or more C1-10 In certain embodiments of Formula IIa, L comprises one or more -C(=O)- groups and one or more -C(=O)- groups. 1-10 In certain embodiments of Formula IIa, L comprises one or more —N(R 2 )- group, one or more -C(=O)- groups, and one or more C 1-10 Contains an alkylene group.

[0203] In certain embodiments of Formula IIa, R 3 together with the L moiety, form a bond between the nitrogen atom and C 2-9 In certain embodiments of Formula IIa, C 2-9 The heterocycle is a 5-, 6-, or 7-membered heterocycle. In certain embodiments of Formula IIa, C 2-9 The heterocycle is a 5-membered heterocycle selected from pyrrolidine, pyrazolidine, and imidazoline. In certain embodiments of Formula IIa, C 2-9 The heterocycle is a 6-membered heterocycle selected from piperazine, hexahydropyrimidine, hexahydropyridazine, 1,2,3-triazinane, 1,2,4-triazinane, and 1,3,5-triazinane. In certain embodiments of Formula IIa, C 2-9 The heterocycle is piperazine.

[0204] In certain embodiments of Formula IIa, R 1 is H or C 1-10 alkyl; R 3 is H; L is up to 20 atoms long, -N(R 2 )-, -O-, -S-, -C(=NR 2 )-, -C(=O)-, C 1-10 Alkylene, C 2-10 Alkenylene, C 3-10 Alkynylene, C 4-10 Cycloalkylene, C 6-10 arylene, and combinations thereof; R 2 independently for each occurrence, H, C 1-10 Alkyl, C 2-10 Alkenyl, C 3-10 Alkynyl, C 3-10Cycloalkyl, C 6-10 Aryl, C 2-9 Heterocyclyl, or C 5-9 heteroaryl, optionally substituted with one or more substituents selected from —OH, —OR′, ═O, ═S, —SH, —SR′, —NH, —NHR′, —N(R′) , —NHCOR′, NR′COR′, halogen, —CN, —COH, —COR′, —CHO, —COR′, —CONH, —CONHR′, —CON(R′) , —NO , —OP(O)(OH) , —SOH, —SOR′, —SOR′, and —SOR′, wherein R′ is independently for each occurrence C 1-10 Alkyl or C 3-10 In certain embodiments of Formula IIa, R 1 is H or C 1-10 alkyl; R 3 is H; L is up to 20 atoms long, -N(R 2 )-, -O-, -C(=O)-, C 1-10 alkylene, and combinations thereof; R 2 and / or each occurrence independently represents H and C 1-10 alkyl.

[0205] In certain embodiments of Formula IIa, R 1 is H or C 1-10 alkyl; R 3 is H, L is up to 20 atoms long, and one or more -N(R 2 )-group, and R 2 is independently for each occurrence H or C 1-10 It is alkyl.

[0206] In certain embodiments of Formula IIa, R 1 is H or C 1-10 alkyl; R 3 is H; L is up to 20 atoms long and contains one or more -C(=O)- groups.

[0207] In certain embodiments of Formula IIa, R 1 is H or C 1-10alkyl; R 3 is H; L is up to 20 atoms long and has one or more C 1-10 Contains an alkylene group.

[0208] In certain embodiments of Formula IIa, R 1 is H or C 1-10 alkyl; R 3 is H; L is up to 20 atoms in length and includes one or more -C(=O)- groups and one or more C 1-10 In certain embodiments of Formula IIa, R 1 is H or C 1-10 alkyl; R 3 is H; L is up to 20 atoms in length and includes one or more -C(=O)- groups and one or more -N(R 2 )-group, and R 2 is independently for each occurrence H or C 1-10 In certain embodiments of Formula IIa, R 1 is H or C 1-10 alkyl; R 3 is H; L is up to 20 atoms long and has one or more C 1-10 an alkylene group and one or more -N(R 2 )-group, and R 2 is independently for each occurrence H or C 1-10 In certain embodiments of Formula IIa, R 1 is H or C 1-10 alkyl; R 3 is H; L is up to 20 atoms in length and includes one or more -C(=O)- groups, one or more C 1-10 an alkylene group and one or more -N(R 2 )-group, and R 2 is independently for each occurrence H or C 1-10 It is alkyl.

[0209] In certain embodiments of Formula IIa, R 1 is H or C 1-10 alkyl; R 3 together with the L moiety to form the nitrogen atom and C to which they are attached. 2-9form a heterocyclic ring, L is up to 20 atoms long, -N(R 2 )-, -O-, -S-, -C(=NR 2 )-, -C(=O)-, C 1-10 Alkylene, C 2-10 Alkenylene, C 3-10 Alkynylene, C 4-10 Cycloalkylene, C 6-10 arylene, and combinations thereof; R 2 independently for each occurrence, H, C 1-10 Alkyl, C 2-10 Alkenyl, C 3-10 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, C 2-9 Heterocyclyl, or C 5-9 heteroaryl, optionally substituted with one or more substituents selected from —OH, —OR′, ═O, ═S, —SH, —SR′, —NH, —NHR′, —N(R′) , —NHCOR′, NR′COR′, halogen, —CN, —COH, —COR′, —CHO, —COR′, —CONH, —CONHR′, —CON(R′) , —NO , —OP(O)(OH) , —SOH, —SOR′, —SOR′, and —SOR′, wherein R′ is independently for each occurrence C 1-10 Alkyl or C 3-10 It is cycloalkyl.

[0210] In certain embodiments of Formula IIa, R 1 is H or C 1-10 alkyl; R 3 together with the L moiety to form the nitrogen atom and C to which they are attached. 2-9 form a heterocyclic ring, L is up to 20 atoms long, and N(R 2 )-, -O-, -C(=O)-, C 1-10 alkylene, and combinations thereof; 2 independently for each occurrence, H and C 1-10alkyl, optionally substituted with one or more substituents selected from —OH, —OR′, ═O, ═S, —SH, —SR′, —NH, —NHR′, —N(R′) , —NHCOR′, NR′COR′, halogen, —CN, —COH, —COR′, —CHO, —COR′, —CONH, —CONHR′, —CON(R′) , —NO , —OP(O)(OH) , —SOH, —SOR′, —SOR′, and —SOR′, wherein R′ is independently for each occurrence C 1-10 Alkyl or C 3-10 It is cycloalkyl.

[0211] In certain embodiments of Formula IIa, R 1 is H or C 1-10 alkyl; R 3 together with the L moiety, form a bond between the nitrogen atom and C 2-9 form a heterocyclic ring; L is up to 20 atoms in length and contains one or more -N(R 2 )-, including the presence of R 2 is, independently for each occurrence, H or C 1-10 It is alkyl.

[0212] The present disclosure also provides still further compounds, including when the compound is a compound of formula III: [ka] R 3 is H, C 1-10 Alkyl, C 2-10 Alkenyl, C 3-10 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, C 2-9 Heterocyclyl, or C 5-9heteroaryl, optionally substituted with one or more substituents selected from —OH, —OR′, ═O, ═S, —SH, —SR′, —NH, —NHR′, —N(R′) , —NHCOR′, —NR′COR′, halogen, —CN, —COH, —COR′, —CHO, —COR′, —CONH, —CONHR′, —CON(R′) , —NO , —OP(O)(OH) , —SOH, —SOR′, —SOR′, and —SOR′; R′ is independently for each occurrence C 1-10 Alkyl or C 3-10 is cycloalkyl; or R 3 together with the L moiety, form a bond between the nitrogen atom and C 2-9 Forming a heterocyclic ring; L is a bivalent linker, preferably up to 20 atoms in length; M is 225 Ac, 51 Cr, 66 Ga, 67 Ga, 68 Ga, [ 18 F]AlF, 111 In, 113m In, 52m Mn, 99m Tc, 186 Re, 188 Re, 139 La, 140 La, 175 Yb, 179 Yb, 153 Sm, 177m Sn, 166 Ho, 86 Y, 88 Y, 90 Y, 149 Pm, 165 Dy, 169 Er, 177 Lu, 52 Fe, 43 Sc, 44 Sc, 46 Sc, 47 Sc, 142 Pr, 157 Gd, 159 Gd, 212 Bi, 213 Bi, 72 As,77 As, 97 Ru, 109 Pd, 105 Rh, 101m Rh, 119 Sb, 197 Hg, 151 EU, 153 EU, 169 EU, 201 Tl, 149 Tb, 152 Tb, 155 Tb, 161 Tb, 203 Pb, 212 Pb, 151 Pm, 153 Pm, 142 Pr, 143 Pr, 55 Co, 60 Cu, 61 Cu, 62 Cu, 64 Cu, 67 Cu, 62 Zn, 188 Re, 198 Au, 199 Au, 227 Th, 111 Ag, 199 Ag, 211 At, 223 Ra, 88 Zr and 89 Selected from Zr; or a pharmaceutically acceptable salt thereof.

[0213] In certain embodiments of Formula III, R 3 is H. In certain embodiments of Formula III, R 3 is C1-C 10 In certain embodiments of Formula III, R 3 is C1-C6 alkyl. In certain embodiments of Formula III, R 3 is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, and hexyl. In certain embodiments of Formula III, R 3 is methyl.

[0214] In certain embodiments of Formula III, L is a bivalent linker as described above for Formula I.

[0215] In certain embodiments of Formula III, L is up to 20 atoms in length. In certain embodiments of Formula III, L is up to 15 atoms in length. In certain embodiments of Formula III, L is up to 10 atoms in length. In certain embodiments of Formula III, L is up to 5 atoms in length.

[0216] In certain embodiments of Formula III, L is —N(R 2 )-, -O-, -S-, -C(=NR 2 )-, -C(=O)-, C 1-10 Alkylene, C 2-10 Alkenylene, C 3-10 Alkynylene, C 4-10 Cycloalkylene, C 6-10 arylene, and combinations thereof; R 2 independently for each occurrence, H, C 1-10 Alkyl, C 2-10 Alkenyl, C 3-10 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, C 2-9 Heterocyclyl, or C 5-9 heteroaryl, optionally substituted with one or more substituents selected from —OH, —OR′, ═O, ═S, —SH, —SR′, —NH, —NHR′, —N(R′) , —NHCOR′, NR′COR′, halogen, —CN, —COH, —COR′, —CHO, —COR′, —CONH, —CONHR′, —CON(R′) , —NO , —OP(O)(OH) , —SOH, —SOR′, —SOR′, and —SOR′, wherein R′ is independently for each occurrence C 1-10 Alkyl or C 3-10 It is cycloalkyl.

[0217] In certain embodiments of Formula III, L is one or more —N(R 2 )-, including R 2 is independently for each occurrence H or C 1-10Alkyl, for example methyl.

[0218] In certain embodiments of Formula III, L contains one or more -C(=O)- groups.

[0219] In certain embodiments of Formula III, L is one or more C 1-10 Contains an alkylene group.

[0220] In certain embodiments of Formula III, L is one or more —N(R 2 In certain embodiments of Formula III, L includes one or more -N(R 2 )-group and one or more C 1-10 In certain embodiments of Formula III, L comprises one or more -C(=O)- groups and one or more C 1-10 In certain embodiments of Formula III, L comprises one or more —N(R 2 )- group, one or more -C(=O)- groups, and one or more C 1-10 Contains an alkylene group.

[0221] In certain embodiments of Formula III, R 3 together with the L moiety, form a bond between the nitrogen atom and C 2-9 In certain embodiments of Formula III, C 2-9 The heterocycle is a 5-, 6-, or 7-membered heterocycle. In certain embodiments of Formula III, C 2-9 The heterocycle is a 5-membered heterocycle selected from pyrrolidine, pyrazolidine, and imidazoline. In certain embodiments of Formula III, C 2-9 The heterocycle is a 6-membered heterocycle selected from piperazine, hexahydropyrimidine, hexahydropyridazine, 1,2,3-triazinane, 1,2,4-triazinane, and 1,3,5-triazinane. In certain embodiments of Formula III, C 2-9 The heterocycle is piperazine.

[0222] In certain embodiments of Formula III, M is 61 Cu, 62 Cu,64 Cu and 67 Cu.

[0223] In certain embodiments of Formula III, R 3 is H; L is up to 20 atoms long, -N(R 2 )-, -O-, -S-, -C(=NR 2 )-, -C(=O)-, C 1-10 Alkylene, C 2-10 Alkenylene, C 3-10 Alkynylene, C 4-10 Cycloalkylene, C 6-10 arylene, and combinations thereof; R 2 independently for each occurrence, H, C 1-10 Alkyl, C 2-10 Alkenyl, C 3-10 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, C 2-9 Heterocyclyl, or C 5-9 heteroaryl, optionally substituted with one or more substituents selected from —OH, —OR′, ═O, ═S, —SH, —SR′, —NH, —NHR′, —N(R′) , —NHCOR′, NR′COR′, halogen, —CN, —COH, —COR′, —CHO, —COR′, —CONH, —CONHR′, —CON(R′) , —NO , —OP(O)(OH) , —SOH, —SOR′, —SOR′, and —SOR′, wherein R′ is independently for each occurrence C 1-10 Alkyl or C 3-10 M is cycloalkyl; 61 Cu, 62 Cu, 64 Cu and 67 In certain embodiments of Formula III, R 3 is H; L is up to 20 atoms long, -N(R 2 )-, -O-, -C(=O)-, C 1-10 alkylene, and combinations thereof; R 2 and / or each occurrence independently represents H and C 1-10alkyl; M is selected from 61 Cu, 62 Cu, 64 Cu and 67 Cu.

[0224] In certain embodiments of Formula III, R 3 is H; L is up to 20 atoms long and is one or more -N(R 2 )-group, and R 2 is independently for each occurrence H or C 1-10 M is alkyl; 61 Cu, 62 Cu, 64 Cu and 67 Cu.

[0225] In certain embodiments of Formula III, R 3 is H; L is up to 20 atoms long and contains one or more C(=O)- groups; M is 61 Cu, 62 Cu, 64 Cu and 67 Cu.

[0226] In certain embodiments of Formula III, R 3 is H; L is up to 20 atoms long and has one or more C 1-10 M contains an alkylene group; 61 Cu, 62 Cu, 64 Cu and 67 Cu.

[0227] In certain embodiments of Formula III, R 3 is H, L is up to 20 atoms long, and has one or more C(=O)- groups and one or more C 1-10 In certain embodiments of Formula III, R 3 is H, L is up to 20 atoms in length, and has one or more -C(=O)- groups and one or more -N(R 2 )-group, and R 2 is independently for each occurrence H or C 1-10 In certain embodiments of Formula III, R3 is H, L is up to 20 atoms long, and one or more C 1-10 an alkylene group and one or more -N(R 2 )-group, and R 2 is independently for each occurrence H or C 1-10 In certain embodiments of Formula III, R 3 is H, L is up to 20 atoms long, and has one or more -C(=O)- groups, one or more C 1-10 an alkylene group and one or more -N(R 2 )-group, and R 2 is independently for each occurrence H or C 1-10 It is alkyl.

[0228] In certain embodiments of Formula III, R 3 together with the L moiety to form the nitrogen atom and C to which they are attached. 2-9 form a heterocyclic ring, L is up to 20 atoms long, -N(R 2 )-, -O-, -S-, -C(=NR 2 )-, -C(=O)-, C 1-10 Alkylene, C 2-10 Alkenylene, C 3-10 Alkynylene, C 4-10 Cycloalkylene, C 6-10 arylene, and combinations thereof; R 2 independently for each occurrence, H, C 1-10 Alkyl, C 2-10 Alkenyl, C 3-10 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, C 2-9 Heterocyclyl, or C 5-9heteroaryl, optionally substituted with one or more substituents selected from —OH, —OR′, ═O, ═S, —SH, —SR′, —NH, —NHR′, —N(R′) , —NHCOR′, NR′COR′, halogen, —CN, —COH, —COR′, —CHO, —COR′, —CONH, —CONHR′, —CON(R′) , —NO , —OP(O)(OH) , —SOH, —SOR′, —SOR′, and —SOR′, wherein R′ is independently for each occurrence C 1-10 Alkyl or C 3-10 cycloalkyl and M is 61 Cu, 62 Cu, 64 Cu and 67 Cu.

[0229] In certain embodiments of Formula III, R 3 together with the L moiety to form the nitrogen atom and C to which they are attached. 2-9 form a heterocyclic ring, L is up to 20 atoms long, and N(R 2 )-, -O-, -C(=O)-, C 1-10 alkylene, and combinations thereof; 2 independently for each occurrence, H and C 1-10 alkyl, optionally substituted with one or more substituents selected from —OH, —OR′, ═O, ═S, —SH, —SR′, —NH, —NHR′, —N(R′) , —NHCOR′, NR′COR′, halogen, —CN, —COH, —COR′, —CHO, —COR′, —CONH, —CONHR′, —CON(R′) , —NO , —OP(O)(OH) , —SOH, —SOR′, —SOR′, and —SOR′, wherein R′ is independently for each occurrence C 1-10 Alkyl or C 3-10 cycloalkyl and M is 61 Cu, 62 Cu, 64 Cu and 67 Cu.

[0230] In certain embodiments of Formula III, R 3together with the L moiety, form a bond between the nitrogen atom and C 2-9 form a heterocyclic ring, L is up to 20 atoms in length, and one or more -N(R 2 )-, including the presence of R 2 is, independently for each occurrence, H or C 1-10 alkyl and M is 61 Cu, 62 Cu, 64 Cu and 67 Cu.

[0231] In certain embodiments of Formula III, the compound is a compound of Formula IIIa: [ka] R 1 is H, C 1-10 Alkyl, C 2-10 Alkenyl, C 3-10 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, C 2-9 Heterocyclyl, or C 5-9 heteroaryl, optionally substituted with one or more substituents selected from —OH, —OR′, ═O, ═S, —SH, —SR′, —NH, —NHR′, —N(R′) , —NHCOR′, —NR′COR′, halogen, —CN, —COH, —COR′, —CHO, —COR′, —CONH, —CONHR′, —CON(R′) , —NO , —OP(O)(OH) , —SOH, —SOR′, —SOR′, and —SOR′; R′ is independently for each occurrence C 1-10 Alkyl or C 3-10 is cycloalkyl, R 3 , L and M are as described above for formula III; or a pharmaceutically acceptable salt thereof.

[0232] In certain embodiments of Formula IIIa, R 1 is H. In certain embodiments of Formula IIIa, R 1 is C1-C 10In certain embodiments of Formula IIIa, R 1 is C1-C6 alkyl. In certain embodiments of Formula IIIa, R 1 is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, and hexyl. In certain embodiments of Formula IIIa, R 1 is methyl.

[0233] In certain embodiments of Formula IIIa, R 3 is H. In certain embodiments of Formula IIIa, R 3 is C1-C 10 In certain embodiments of Formula IIIa, R 3 is C1-C6 alkyl. In certain embodiments of Formula IIIa, R 3 is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, and hexyl. In certain embodiments of Formula IIIa, R 3 is methyl.

[0234] In certain embodiments of Formula IIIa, R 3 together with the L moiety, form a bond between the nitrogen atom and C 2-9 In certain embodiments of Formula IIIa, C 2-9 The heterocycle is a 5-, 6-, or 7-membered heterocycle. In certain embodiments of Formula IIIa, C 2-9 The heterocycle is a 5-membered heterocycle selected from pyrrolidine, pyrazolidine, and imidazoline. In certain embodiments of Formula IIIa, C 2-9 The heterocycle is a 6-membered heterocycle selected from piperazine, hexahydropyrimidine, hexahydropyridazine, 1,2,3-triazinane, 1,2,4-triazinane, and 1,3,5-triazinane. In certain embodiments of Formula IIIa, C 2-9 The heterocycle is piperazine.

[0235] In certain embodiments of Formula IIIa, L is a bivalent linker as described above for Formula I.

[0236] In certain embodiments of Formula IIIa, L is up to 20 atoms in length. In certain embodiments of Formula IIIa, L is up to 15 atoms in length. In certain embodiments of Formula IIIa, L is up to 10 atoms in length. In certain embodiments of Formula IIIa, L is up to 5 atoms in length.

[0237] In certain embodiments of Formula IIIa, L is —N(R 2 )-, -O-, -S-, -C(=NR 2 )-, -C(=O)-, C 1-10 Alkylene, C 2-10 Alkenylene, C 3-10 Alkynylene, C 4-10 Cycloalkylene, C 6-10 arylene, and combinations thereof; R 2 independently for each occurrence, H, C 1-10 Alkyl, C 2-10 Alkenyl, C 3-10 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, C 2-9 Heterocyclyl, or C 5-9 heteroaryl, optionally substituted with one or more substituents selected from —OH, —OR′, ═O, ═S, —SH, —SR′, —NH, —NHR′, —N(R′) , —NHCOR′, NR′COR′, halogen, —CN, —COH, —COR′, —CHO, —COR′, —CONH, —CONHR′, —CON(R′) , —NO , —OP(O)(OH) , —SOH, —SOR′, —SOR′, and —SOR′, wherein R′ is independently for each occurrence C 1-10 Alkyl or C 3-10 It is cycloalkyl.

[0238] In certain embodiments of Formula IIIa, L is one or more —N(R 2 )-, including R 2 is independently for each occurrence H or C 1-10 Alkyl, for example methyl.

[0239] In certain embodiments of Formula IIIa, L contains one or more -C(=O)- groups.

[0240] In certain embodiments of Formula IIIa, L is one or more C 1-10 Contains an alkylene group.

[0241] In certain embodiments of Formula IIIa, L is one or more —N(R 2 In certain embodiments of Formula IIIa, L includes one or more —N(R 2 )-group and one or more C 1-10 In certain embodiments of Formula IIIa, L comprises one or more -C(=O)- groups and one or more C 1-10 In certain embodiments of Formula IIIa, L comprises one or more —N(R 2 )- group, one or more -C(=O)- groups, and one or more C 1-10 Contains an alkylene group.

[0242] In certain embodiments of Formula IIIa, R 3 together with the L moiety, form a bond between the nitrogen atom and C 2-9 In certain embodiments of Formula IIIa, C 2-9 The heterocycle is a 5-, 6-, or 7-membered heterocycle. In certain embodiments of Formula IIIa, C 2-9 The heterocycle is a 5-membered heterocycle selected from pyrrolidine, pyrazolidine, and imidazoline. In certain embodiments of Formula IIIa, C 2-9 The heterocycle is a 6-membered heterocycle selected from piperazine, hexahydropyrimidine, hexahydropyridazine, 1,2,3-triazinane, 1,2,4-triazinane, and 1,3,5-triazinane. In certain embodiments of Formula IIIa, C 2-9 The heterocycle is piperazine.

[0243] In certain embodiments of Formula IIIa, M is 61 Cu, 62 Cu, 64 Cu and 67 Cu.

[0244] In certain embodiments of Formula IIIa, R 1 is H or C 1-10 alkyl; R 3 is H; L is up to 20 atoms long, -N(R 2 )-, -O-, -S-, -C(=NR 2 )-, -C(=O)-, C 1-10 Alkylene, C 2-10 Alkenylene, C 3-10 Alkynylene, C 4-10 Cycloalkylene, C 6-10 arylene, and combinations thereof; R 2 independently for each occurrence, H, C 1-10 Alkyl, C 2-10 Alkenyl, C 3-10 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, C 2-9 Heterocyclyl, or C 5-9 heteroaryl, optionally substituted with one or more substituents selected from —OH, —OR′, ═O, ═S, —SH, —SR′, —NH, —NHR′, —N(R′) , —NHCOR′, NR′COR′, halogen, —CN, —COH, —COR′, —CHO, —COR′, —CONH, —CONHR′, —CON(R′) , —NO , —OP(O)(OH) , —SOH, —SOR′, —SOR′, and —SOR′, wherein R′ is independently for each occurrence C 1-10 Alkyl or C 3-10 M is cycloalkyl; 61 Cu, 62 Cu, 64 Cu and 67 In certain embodiments of Formula IIIa, R 1 is H or C 1-10 alkyl; R 3 is H; L is up to 20 atoms long, -N(R 2 )-, -O-, -C(=O)-, C 1-10 alkylene, and combinations thereof; R2 and / or each occurrence independently represents H and C 1-10 alkyl; M is selected from 61 Cu, 62 Cu, 64 Cu and 67 Cu.

[0245] In certain embodiments of Formula IIIa, R 1 is H or C 1-10 alkyl; R 3 is H; L is up to 20 atoms long and is one or more -N(R 2 )-group, and R 2 is independently for each occurrence H or C 1-10 M is alkyl; 61 Cu, 62 Cu, 64 Cu and 67 Cu.

[0246] In certain embodiments of Formula IIIa, R 1 is H or C 1-10 alkyl; R 3 is H; L is up to 20 atoms long and contains one or more C(=O)- groups; M is 61 Cu, 62 Cu, 64 Cu and 67 Cu.

[0247] In certain embodiments of Formula IIIa, R 1 is H or C 1-10 alkyl; R 3 is H; L is up to 20 atoms long and has one or more C 1-10 M contains an alkylene group; 61 Cu, 62 Cu, 64 Cu and 67 Cu.

[0248] In certain embodiments of Formula IIIa, R 1 is H or C 1-10 alkyl; R 3is H; L is up to 20 atoms in length and includes one or more -C(=O)- groups and one or more C 1-10 In certain embodiments of Formula IIIa, R 1 is H or C 1-10 alkyl; R 3 is H; L is up to 20 atoms in length and includes one or more -C(=O)- groups and one or more -N(R 2 )-group, and R 2 is independently for each occurrence H or C 1-10 In certain embodiments of Formula IIIa, R 1 is H or C 1-10 alkyl; R 3 is H; L is up to 20 atoms long and has one or more C 1-10 an alkylene group and one or more -N(R 2 )-group, and R 2 is independently for each occurrence H or C 1-10 In certain embodiments of Formula IIIa, R 1 is H or C 1-10 alkyl; R 3 is H; L is up to 20 atoms in length and includes one or more -C(=O)- groups, one or more C 1-10 an alkylene group and one or more -N(R 2 )-group, and R 2 is independently for each occurrence H or C 1-10 It is alkyl.

[0249] In certain embodiments of Formula IIIa, R 1 is H or C 1-10 alkyl; R 3 together with the L moiety to form the nitrogen atom and C to which they are attached. 2-9 form a heterocyclic ring, L is up to 20 atoms long, -N(R 2 )-, -O-, -S-, -C(=NR 2 )-, -C(=O)-, C 1-10 Alkylene, C 2-10 Alkenylene, C 3-10 Alkynylene, C 4-10 Cycloalkylene, C 6-10arylene, and combinations thereof; R 2 independently for each occurrence, H, C 1-10 Alkyl, C 2-10 Alkenyl, C 3-10 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, C 2-9 Heterocyclyl, or C 5-9 heteroaryl, optionally substituted with one or more substituents selected from —OH, —OR′, ═O, ═S, —SH, —SR′, —NH, —NHR′, —N(R′) , —NHCOR′, NR′COR′, halogen, —CN, —COH, —COR′, —CHO, —COR′, —CONH, —CONHR′, —CON(R′) , —NO , —OP(O)(OH) , —SOH, —SOR′, —SOR′, and —SOR′, wherein R′ is independently for each occurrence C 1-10 Alkyl or C 3-10 M is cycloalkyl; 61 Cu, 62 Cu, 64 Cu and 67 Cu.

[0250] In certain embodiments of Formula IIIa, R 1 is H or C 1-10 alkyl; R 3 together with the L moiety to form the nitrogen atom and C to which they are attached. 2-9 form a heterocyclic ring, L is up to 20 atoms long, and N(R 2 )-, -O-, -C(=O)-, C 1-10 alkylene, and combinations thereof; 2 independently for each occurrence, H and C 1-10alkyl, optionally substituted with one or more substituents selected from —OH, —OR′, ═O, ═S, —SH, —SR′, —NH, —NHR′, —N(R′) , —NHCOR′, NR′COR′, halogen, —CN, —COH, —COR′, —CHO, —COR′, —CONH, —CONHR′, —CON(R′) , —NO , —OP(O)(OH) , —SOH, —SOR′, —SOR′, and —SOR′, wherein R′ is independently for each occurrence C 1-10 Alkyl or C 3-10 M is cycloalkyl; 61 Cu, 62 Cu, 64 Cu and 67 Cu.

[0251] In certain embodiments of Formula IIIa, R 1 is H or C 1-10 alkyl; R 3 together with the L moiety, form a bond between the nitrogen atom and C 2-9 form a heterocyclic ring, L is up to 20 atoms in length, and one or more -N(R 2 )-, including the presence of R 2 is, independently for each occurrence, H or C 1-10 M is alkyl; 61 Cu, 62 Cu, 64 Cu and 67 Cu.

[0252] 3. Composition In another aspect, the present disclosure provides compositions (e.g., pharmaceutical compositions) comprising one or more compounds of Formulas I-III above and one or more pharmaceutically acceptable excipients.

[0253] Pharmaceutical compositions can be prepared by methods well known in the pharmaceutical field.Excipients must be acceptable in the sense that they are compatible with other components of the composition and are not harmful to the recipient.According to another aspect of the present disclosure, there is also provided a process for preparing pharmaceutical compositions comprising the provided compound or its pharmaceutically acceptable salts together with one or more pharmaceutically acceptable excipients.The pharmaceutical composition can be used for the diagnosis, treatment and / or prevention of any of the conditions described herein.

[0254] Generally, the pharmaceutical compositions provided are administered in an effective amount. The amount to be administered is typically determined by a physician in light of the relevant circumstances, including the condition to be treated (e.g., a therapeutically effective amount) or the image to be generated (e.g., a diagnostically effective amount), the selected route of administration, the pharmaceutical composition to be administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, etc.

[0255] Pharmaceutical compositions can be provided in unit dosage forms, which contain a predetermined amount of active ingredient per unit dosage.The term "unit dosage form" refers to a physically separate unit suitable for human subjects and other mammals as a unit dosage, and each unit contains a predetermined amount of active material calculated to produce desired therapeutic effect, combined with suitable pharmaceutical excipients, vehicles or carriers.Typical unit dosage forms include pre-filled and pre-measured ampoules or syringes of liquid compositions, or pills, tablets, capsules, etc. for solid compositions.

[0256] Preferred unit dosage compositions are those that contain the daily dose or part-dose of active ingredient or its appropriate proportion.Therefore, such unit dosage can be administered once or multiple times a day.Such pharmaceutical composition can be prepared by any method well known in the field of pharmacy.

[0257] Pharmaceutical compositions may be adapted for administration by any suitable route, for example, oral (including buccal or sublingual), rectal, inhalation, intranasal, topical (including buccal, sublingual, or transdermal), vaginal, or parenteral (including subcutaneous, intramuscular, intravenous, or intradermal) routes. Such compositions may be prepared by any method known in the art of pharmacy, for example, by bringing into association the active ingredient with the carrier(s) or excipient(s).

[0258] In certain embodiments, the pharmaceutical composition comprises a preservative. In certain embodiments, suitable preservatives may include, for example, methylparaben, propylparaben, sodium benzoate, and benzalkonium chloride.

[0259] In certain embodiments, the pharmaceutical composition comprises a buffering agent. In certain embodiments, suitable buffering agents may include, for example, citric acid, sodium citrate, phosphoric acid, potassium phosphate, and various other acids and salts.

[0260] In certain embodiments, the pharmaceutical composition is administered parenterally (eg, subcutaneously, intravenously, intraarterially, intramuscularly, intradermally, intraperitoneally, intrathecally, or intraocularly).

[0261] Parenteral pharmaceutical compositions may be presented in unit-dose or multi-dose sealed containers such as ampoules or vials and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of a sterile liquid vehicle, for example, water for injections, immediately prior to use.

[0262] In certain embodiments, provided herein is injectable pharmaceutical compositions.The requirements of effective pharmaceutical carrier for injectable compositions are well known to those skilled in the art (see, for example, "Pharmaceutics and Pharmacy Practice" JBLippincott Company, Philadelphia, PA, Banker and Chalmers, eds., pages 238-250 (1982) and "ASHP ​​Handbook on Injectable Drugs" Toissel, 4th ed, pages 622-630 (1986)).

[0263] In certain embodiments, pharmaceutical compositions according to the present disclosure are characterized by one or more of the radioactivity and purity characteristics described below.

[0264] radioactivity The term "radioactivity" (also called activity or total activity) is a physical quantity defined as the number of radioactive transformations per second that occur in a particular radionuclide. The unit of radioactivity used herein is the becquerel (symbol Bq), which is expressed as the reciprocal of 1 / s or s -1 ) is defined as equivalent to

[0265] molar radioactivity The term "molar radioactivity" is defined as the amount of radioactivity per mole (e.g., nuclear disintegrations per second) of a radiolabeled compound, expressed in Bq / mol, e.g., GBq / μmol, and is used when the molecular weight of the labeled material is known.

[0266] In certain embodiments, the molar radioactivity of the composition is between 1 and 280 MBq / nmol, e.g., between 5 and 265 MBq / nmol, 10 and 250 MBq / nmol, 15 and 235 MBq / nmol, 20 and 220 MBq / nmol, 25 and 205 MBq / nmol, 30 and 190 MBq / nmol, 35 and 175 MBq / nmol, 40 and 160 MBq / nmol, 45 and 150 MBq / nmol, 50 and 135 MBq / nmol , 55-120 MBq / nmol, 1-50 MBq / nmol, 2-48 MBq / nmol, 4-46 MBq / nmol, 6-44 MBq / nmol, 8-42 MBq / nmol, 10-40 MBq / nmol, 12-38 MBq / nmol, 14-36 MBq / nmol, 16-34 MBq / nmol, 18-32 MBq / nmol, 20-30 MBq / nmol, or 22-28 MBq / nmol. In certain embodiments, the composition has a molar radioactivity of 24 MBq / nmol±3 MBq / nmol.

[0267] In certain embodiments, the molar radioactivity of the composition is 35 MBq / nmol or greater, 40 MBq / nmol or greater, 45 MBq / nmol or greater, 50 MBq / nmol or greater, 55 MBq / nmol or greater, 60 MBq / nmol or greater, 65 MBq / nmol or greater, 70 MBq / nmol or greater, 75 MBq / nmol or greater, 80 MBq / nmol or greater, 85 MBq / nmol or greater, 90 MBq / nmol or greater, 95 MBq / nmol or greater, 100 MBq / nmol or greater, 105 MBq / nmol or greater, 110 MBq / nmol or greater, 115 MBq / nmol or greater. , 120MBq / nmol or more, 125MBq / nmol or more, 130MBq / nmol or more, 135MBq / nmol or more, 140MBq / nmol or more, 145MBq / nmol or more, 150MBq / nmol or more, 155MBq / nmol or more, 160MBq / nmol or more, 165MBq / nmol or more, 170MBq / nmol or more, 175MBq / nmol or more, 180MBq / nmol or more, 185MBq / nmol or more, 190MBq / nmol or more, 195MBq / nmol or more, or 200MBq / nmol or more.

[0268] In certain embodiments, the molar radioactivity of the composition is 1 to 250 MBq / nmol, e.g., 1 to 200 MBq / nmol, 1 to 150 MBq / nmol, 1 to 100 MBq / nmol, 1 to 50 MBq / nmol, 50 to 250 MBq / nmol, 50 to 200 MBq / nmol, 50 to 150 MBq / nmol, 50 to 100 MBq / nmol, 100 to 250 MBq / nmol, 100 to 150 MBq / nmol, 150 to 250 MBq / nmol, 150 to 200 MBq / nmol, or 200 to 250 MBq / nmol. In certain embodiments, the composition is characterized by a molar radioactivity of 1 to 150 MBq / nmol.

[0269] In certain embodiments, the molar radioactivity of the composition is 90 MBq / nmol or more, 88 MBq / nmol or more, 86 MBq / nmol or more, 84 MBq / nmol or more, 82 MBq / nmol or more, 80 MBq / nmol or more, 78 MBq / nmol or more, 76 MBq / nmol or more, 74 MBq / nmol or more, 72 MBq / nmol or more, 70 MBq / nmol or more, 68 MBq / nmol or more, 66 MBq / nmol or more, 64 MBq / nmol or more, 62 MBq / nmol or more, 60 MBq / nmol or more, 58 MBq / nmol or more, 56 MBq / nmol or more, 54 MBq / nmol or more, 52 MBq / nmol or more, 50 MBq / nmol or more, 48 MBq / nmol or more, 46 MBq / nmol or more, 44 MBq / nmol or more, or 42 MBq / nmol or more.

[0270] In certain embodiments, the molar radioactivity of the composition is 3 MBq / nmol or more, 4 MBq / nmol or more, 5 MBq / nmol or more, 6 MBq / nmol or more, 7 MBq / nmol or more, 8 MBq / nmol or more, 9 MBq / nmol or more, 10 MBq / nmol or more, 11 MBq / nmol or more, 12 MBq / nmol or more, 13 MBq / nmol or more, 14 MBq / nmol or more, 15 MBq / nmol or more, 16 MBq / nmol or more, 17 MBq / nmol or more, 18 MBq / nmol or more, or 19 MBq / nmol or more.

[0271] In certain embodiments, the molar radioactivity of the composition is 3 MBq / nmol or greater, 5 MBq / nmol or greater, 10 MBq / nmol or greater, 15 MBq / nmol or greater, 20 MBq / nmol or greater, 25 MBq / nmol or greater, 30 MBq / nmol or greater, 35 MBq / nmol or greater, 40 MBq / nmol or greater, 45 MBq / nmol or greater, 50 MBq / nmol or greater, 55 MBq / nmol or greater, 60 MBq / nmol or greater, 65 MBq / nmol 70MBq / nmol or more, 75MBq / nmol or more, 80MBq / nmol or more, 85MBq / nmol or more, 90MBq / nmol or more, 95MBq / nmol or more, 100MBq / nmol or more, 105M Bq / nmol or more, 110MBq / nmol or more, 115MBq / nmol or more, 120MBq / nmol or more, 125MBq / nmol or more, 130MBq / nmol, 135MBq / nmol, 140MBq / nm ol, 145MBq / nmol or more, 150MBq / nmol, 155MBq / nmol, 160MBq / nmol or more, 165MBq / nmol or more, 170MBq / nmol or more, 175MBq / nmol or more, 18 0MBq / nmol or more, 185MBq / nmol or more, 190MBq / nmol or more, 195MBq / nmol or more, 200MBq / nmol or more, 205MBq / nmol or more, 210MBq / nmol or more, 215 In certain embodiments, the composition has a molar radioactivity of 24 MBq / nmol or greater, 220 MBq / nmol or greater, 225 MBq / nmol or greater, 230 MBq / nmol or greater, 235 MBq / nmol or greater, 240 MBq / nmol or greater, 245 MBq / nmol or greater, 250 MBq / nmol or greater, 255 MBq / nmol or greater, 260 MBq / nmol or greater, 265 MBq / nmol or greater, 270 MBq / nmol or greater, 275 MBq / nmol or greater, or 280 MBq / nmol or greater.

[0272] In certain embodiments, the molar radioactivity of the composition is 1 to 250 MBq / nmol, e.g., 1 to 200 MBq / nmol, 1 to 150 MBq / nmol, 1 to 100 MBq / nmol, 1 to 50 MBq / nmol, 50 to 250 MBq / nmol, 50 to 200 MBq / nmol, 50 to 150 MBq / nmol, 50 to 100 MBq / nmol, 100 to 250 MBq / nmol, 100 to 150 MBq / nmol, 150 to 250 MBq / nmol, 150 to 200 MBq / nmol, or 200 to 250 MBq / nmol.

[0273] radioactivity concentration Radioactivity concentration is the total amount of radioactivity per unit volume. In certain embodiments, radioactivity concentration is expressed in Bq / L or its magnitude (e.g., MBq / mL).

[0274] In certain embodiments, the compositions provided herein are characterized by a radioactivity concentration of 8 MBq / mL or greater. In certain embodiments, the compositions provided herein are characterized by a radioactivity concentration of 8-10 MBq / mL, 10-20 MBq / mL, 20-30 MBq / mL, 30-40 MBq / mL, 40-50 MBq / mL, 50-60 MBq / mL, 60-70 MBq / mL, 70-80 MBq / mL, 80-90 MBq / mL, 90-100 MBq / mL, 100-110 MBq / mL, 110-120 MBq / mL, 120-130 MBq / mL, 130-140 MBq / mL, 140-150 MBq / mL, 150-160 MBq / mL, 160-170 MBq / mL, or any combination thereof. 250 ~260MBq / mL, 260~270MBq / mL, 270~280MBq / mL, 280~290MBq / mL, 290~300MBq / mL, 300~310MBq / mL, 310~320MBq / mL, 320~330MBq / mL, 330~340MBq / mL, 340~350MBq / mL, 350~360MBq / mL, 360~370MBq / mL, 370~380MBq / mL, 380~390MBq / mL, 390~400MBq / mL, 400~410MBq / mL, 410~420MBq / mL, 420~ 430MBq / mL, 430~440MBq / mL, 440~450MBq / mL, 450~460MBq / mL, 460~470MBq / mL, 470~480MBq / mL, 480~490MBq / mL, 490~500MBq / mL, 500~510MBq / m L, 510~520MBq / mL, 520~530MBq / mL, 530~540MBq / mL, 540~550MBq / mL, 550~560MBq / mL, 560~570MBq / mL, 570~580MBq / mL, 580~590MBq / mL, 590~60 0MBq / mL, 600~610MBq / mL, 610~620MBq / mL, 620~630MBq / mL, 630~640MBq / mL, 640~650MBq / mL, 650~660MBq / mL, 660~670MBq / mL, 670~680MBq / mL,680~690MBq / mL, 690~700MBq / mL, 700~710MBq / mL, 710~720MBq / mL, 720~730MBq / mL, 730~740MBq / mL, 740~750MBq / mL, 750~760MBq / mL, 760 ~770MBq / mL, 770~780MBq / mL, 780~790MBq / mL, 790~800MBq / mL, 800~810MBq / mL, 810~820MBq / mL, 820~830MBq / mL, 830~840MBq / mL, 840~850 The radioactivity concentration is 850-860MBq / mL, 860-870MBq / mL, 870-880MBq / mL, 880-890MBq / mL, 890-900MBq / mL, 900-910MBq / mL, 910-920MBq / mL, 920-930MBq / mL, 930-940MBq / mL, 940-950MBq / mL, 950-960MBq / mL, 960-970MBq / mL, 970-980MBq / mL, 980-990MBq / mL or 990-1000MBq / mL.

[0275] In certain embodiments, the provided composition has a radioactivity concentration of 8 MBq / mL or greater, 5 to 500 MBq / mL, 20 to 480 MBq / mL, 40 to 460 MBq / mL, 60 to 440 MBq / mL, 80 to 420 MBq / mL, 100 to 400 MBq / mL, 120 to 380 MBq / mL, 140 to 360 MBq / mL, 160 to 340 MBq / mL, 180 to 320 MBq / mL, or 200 to 300 MBq / mL.

[0276] In certain embodiments, the radioactivity concentration of the composition is 3 MBq / mL or greater, 4 MBq / mL or greater, 5 MBq / mL or greater, 6 MBq / mL or greater, 7 MBq / mL or greater, 8 MBq / mL or greater, 9 MBq / mL or greater, 10 MBq / mL or greater, 12 MBq / mL or greater, 15 MBq / mL or greater, 20 MBq / mL or greater, 25 MBq / mL or greater, 30 MBq / mL or greater, 35 MBq / mL or greater, 40 MBq / mL or greater, 45 MBq / mL or greater or more, 50MBq / mL or more, 55MBq / mL or more, 60MBq / mL or more, 65MBq / mL or more, 70MBq / mL or more, 75MBq / mL or more, 80MBq / mL or more, 85MBq / mL or more, 90 13 0MBq / mL or more, 135MBq / mL or more, 140MBq / mL or more, 145MBq / mL or more, 150MBq / mL or more, 155MBq / mL or more, 160MBq / mL or more, 165MBq / mL or more , 170MBq / mL or more, 175MBq / mL or more, 180MBq / mL or more, 185MBq / mL or more, 190MBq / mL or more, 195MBq / mL or more, 200MBq / mL or more, 205MBq / mL or more, 210MBq / mL or more, 215MBq / mL or more, 220MBq / mL or more, 225MBq / mL or more, 230MBq / mL or more, 235MBq / mL or more, 240MBq / mL or more, 245MBq / mL or more, 250MBq / mL or more, 255MBq / mL or more, 260MBq / mL or more, 265MBq / mL or more, 270MBq / mL or more, 275MBq / mL or more, or 280MBq / mL or more.

[0277] In certain embodiments, the radioactivity concentration of the resulting pharmaceutical composition may be diluted (e.g., 3- to 10-fold) as long as the radioactivity concentration is 8 MBq / mL or higher. In certain embodiments, the radioactivity concentration of the composition is 8-20 MBq / mL, 9-19 MBq / mL, 10-18 MBq / mL, 11-19 MBq / mL, 12-18 MBq / mL, 13-15 MBq / mL, 14-15 MBq / mL, 8-14 MBq / mL, 8-13 MBq / mL, 8-12 MBq / mL, 8-11 MBq / mL, 8-10 MBq / mL, 8-9 MBq / mL, 9-14 MBq / mL, 10-13 MBq / mL, or 11-12 MBq / mL.

[0278] radiochemical purity "Radiochemical purity," as understood herein, is the ratio, given as a percentage, of the radioactivity from the desired radionuclide in a radiopharmaceutical composition (e.g., the desired radionuclide chelated with a radiotracer described herein) to the total radioactivity of the composition containing the radiopharmaceutical. It is important to know that the majority of the radioisotope is bound to the tracer construct and not free or bound to another chemical entity, because these forms may have different biodistributions. Radiochemical purity (RCP) measurements establish the content of impurities labeled with the same radionuclide but in a different chemical form than that used to prepare the radiopharmaceutical. For most radiopharmaceuticals, the lower limit of radiochemical purity is 95%, i.e., at least 95% of the radioisotope must be bound to the ligand. Radiochemical purity determination can be performed by various chromatographic methods.

[0279] Radiochemical purity is determined according to methods well known to those skilled in the art, such as radio-HPLC, iTLC, and / or γ-spectrometry. As understood in the art, the determination of radiochemical purity is not strictly quantitative but is calculated as the ratio of the peak area of ​​the desired radiopharmaceutical to the total area (decay-corrected) of all peaks detected in the radiochromatogram. The instrument used to determine radiochemical purity using HPLC (radio-HPLC) is a radiometric detector (radiodetector) with an in-line detector connected in series with a UV or other physicochemical detector. The radiation detector can be a Geiger-Muller probe, a scintillation detector, or a PIN diode. Compared to radio-HPLC, it has the significant advantage that all applied radioactivity is detected and there are no concerns about recovery.

[0280] In certain embodiments, the composition is characterized by a radiochemical purity of 90% or greater. In certain embodiments, the composition is characterized by a radiochemical purity of 91% or greater. In certain embodiments, the composition is characterized by a radiochemical purity of 95% or greater, 96% or greater, 97% or greater, 98% or greater, or 99% or greater. In certain embodiments, the composition is characterized by a radiochemical purity of 90% or greater. In certain embodiments, the composition is characterized by a radiochemical purity of 95% or greater. In certain embodiments, the composition is characterized by a radiochemical purity of 96% or greater. In certain embodiments, the composition is characterized by a radiochemical purity of 98% or greater.

[0281] In certain embodiments, provided compositions are characterized by a radiochemical purity of 94.0% or greater, 94.5% or greater, 95.0% or greater, 95.5% or greater, 96.0% or greater, 96.5% or greater, 97.0% or greater, 97.5% or greater, 98.0% or greater, 98.5% or greater, 99.0% or greater, or 99.5% or greater.

[0282] In certain embodiments, provided compositions are characterized by a radiochemical purity of 95.2% or greater, 95.4% or greater, 95.6% or greater, 95.8% or greater, 96% or greater, 96.2% or greater, 96.4% or greater, 96.6% or greater, 96.8% or greater, 97% or greater, 97.2% or greater, 97.4% or greater, 97.6% or greater, 97.8% or greater, 98% or greater, 98.2% or greater, 98.4% or greater, 98.6% or greater, 98.8% or greater, 99% or greater, 99.2% or greater, 99.4% or greater, 99.6% or greater, or 99.8% or greater.

[0283] Radionuclide purity The term "radionuclide purity" refers to the ratio, expressed as a percentage, of the radioactivity of a desired radionuclide to the total radioactivity of starting materials used to prepare a sample, e.g., a radiolabeled pharmaceutical. As reported herein, unless otherwise specified, radionuclide purity is determined by high-resolution gamma spectroscopy (e.g., a high-purity germanium (HPGe) detector) of the sample post-exhalation, e.g., >8 hours or >3 weeks), and then extrapolated (e.g., using the TENDLE-2019 database according to procedures well known in the art) and reported herein as the value at the end of synthesis of the radionuclide (EoB + 2 hours).

[0284] In certain embodiments, the composition is characterized in that the radionuclide purity of the compound at the end of synthesis is 85% or greater, e.g., 86% or greater, 87% or greater, 88% or greater, 89% or greater, 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, or 99% or greater.

[0285] In certain embodiments, the composition is characterized in that the radionuclide purity of the compound at the end of synthesis is 90.5% or greater, e.g., 91% or greater, 91.5% or greater, 92% or greater, 92.5% or greater, 93% or greater, 93.5% or greater, 94% or greater, 94.5% or greater, 95% or greater, 95.5% or greater, 96% or greater, 96.5% or greater, 97% or greater, 97.5% or greater, 98% or greater, 98.5% or greater, 99% or greater, or 99.5% or greater.

[0286] In certain embodiments, the composition has a cytoplasmic ... Characterized by a radionuclide purity of ≥5%, ≥97.6%, ≥97.7%, ≥97.8%, ≥97.9%, ≥98%, ≥98.1%, ≥98.2%, ≥98.3%, ≥98.4%, ≥98.5%, ≥98.6%, ≥98.7%, ≥98.8%, ≥98.9%, ≥99%, ≥99.1%, ≥99.2%, ≥99.3%, ≥99.4%, ≥99.5%, ≥99.6%, ≥99.7%, ≥99.8%, or ≥99.9%.

[0287] In certain embodiments, the composition is characterized by a radionuclide purity of 97% or greater (at the end of synthesis). In certain embodiments, the composition is characterized by a radionuclide purity of 93% or greater, 94% or greater, 95% or greater, 96% or greater, 98% or greater, or 99% or greater (at the end of synthesis).

[0288] 4.How to use In one aspect, the present disclosure provides compounds and pharmaceutical compositions comprising same for use in medicine, i.e., for use in treatment, imaging, diagnosis, companion diagnostics, etc. The present disclosure further provides the use of any compound or pharmaceutical composition described herein for targeted radiation therapy, which would be beneficial in diagnosing and / or treating cancer.

[0289] In certain embodiments, the compound or pharmaceutical composition of the present disclosure is administered to a subject once a day, twice a day, every day, or every other day. In certain embodiments, the compound or pharmaceutical composition of the present disclosure is administered to a subject twice a week, once a week, every 10 days, every 2 weeks, every 3 weeks, every 4 weeks, every month, every 6 weeks, every 8 weeks, every 3 months, every 4 months, every 6 months, every 8 months, every 9 months, or every year. The dose and frequency (single dose or multiple doses) of the compound or pharmaceutical composition administered can vary depending on various factors, including the route of administration; the recipient's size, age, sex, health, weight, body mass index, and diet; the nature and severity of the symptoms of the disease being treated (e.g., disease-responsive treatment) and complications from any disease or treatment regimen. Other treatment regimens or drugs can be used in conjunction with the methods and compounds of the present invention.

[0290] For any compound or pharmaceutical composition provided, the effective amount (e.g., a diagnostically or therapeutically effective amount) can be initially determined from cell culture assays and / or animal studies. The target concentration is the concentration of the radioactive compound that is capable of diagnosing, monitoring, and / or treating cancer in a patient or subject.

[0291] The therapeutic efficacy of a compound may be determined from animal models. Human dosages can be adjusted during clinical trials via dose escalation studies by monitoring safety and efficacy.

[0292] Dosage can vary depending on the requirements of the patient and the compound or pharmaceutical composition used.In the context of the present invention, the dosage administered to a patient should be sufficient to affect beneficial therapeutic responses in the patient over time.The size of the dosage will also be determined by the existence, nature and extent of adverse side effects.

[0293] In one aspect, the compounds provided herein exhibit one or more improved pharmacokinetic (PK) properties (e.g., C max , t max , Cmin , t 1 / 2 , AUC, CL, bioavailability, etc.)

[0294] In some embodiments, a compound of the present disclosure or a pharmaceutical composition comprising same is provided as a unit dose.

[0295] 4.4.1. Imaging and Diagnostics In one aspect of the present disclosure, a method for generating an image of a subject (e.g., of a specific region or portion of the subject's body) is provided, the method comprising administering to the subject a compound described herein that comprises a radionuclide. In certain embodiments, the radionuclide is a metallic radionuclide. In certain embodiments, the radionuclide is 60 Cu, 61 Cu, 62 Cu, 64 Cu and 67 In certain embodiments, the radionuclide is selected from Cu. 61 In certain embodiments, the radionuclide is Cu. 67 It is Cu.

[0296] In certain embodiments, a method for generating one or more images of a subject (e.g., of a particular region or portion of the subject's body) is provided, the method comprising administering to the subject an effective amount of a compound comprising a radionuclide as described herein or a pharmaceutical composition comprising the same, and generating one or more images of at least a portion of the subject's body. In certain embodiments, two or more images of the subject are generated, e.g., three or more images, four or more images, or five or more images. In certain embodiments, a diagnostically effective amount of a compound comprising a radionuclide or a pharmaceutical composition comprising the same, i.e., an amount sufficient to identify (visually or computationally) the localization of the radionuclide within a region or portion of the subject's body, is administered to the subject. In some embodiments, the radionuclide is a metallic radionuclide. In certain embodiments, the radionuclide is 60 Cu, 61 Cu, 62 Cu, 64 Cu and 67 In some embodiments, the radionuclide is selected from Cu.61 It is Cu.

[0297] In certain embodiments, the one or more images are generated using positron emission tomography (PET). In certain embodiments, the one or more images are generated using PET-computed tomography (PET-CT). In certain embodiments, the one or more images are generated using single-photon emission computed tomography (SPECT).

[0298] In certain embodiments, the images are generated using PET or PET-CT, and the radionuclide is 61 In certain embodiments, the image is 61 Cu or 67 Generated using SPECT, which is Cu.

[0299] In certain embodiments, after one or more images are generated, the method further includes determining the presence or absence of disease in the subject based on the presence or absence of localization of the radionuclide in the one or more images of the subject's body.

[0300] In certain embodiments, the disease is cancer. In certain embodiments, the cancer is selected from breast cancer (e.g., triple-negative breast cancer), pancreatic cancer, small intestine cancer, colon cancer, gastric cancer, rectal cancer, lung cancer (e.g., non-small cell lung cancer), head and neck cancer, ovarian cancer, hepatocellular carcinoma, epithelial cancer, esophageal cancer, hypopharyngeal cancer, nasopharyngeal carcinoma, laryngeal cancer, myeloma cells, bladder cancer, cholangiocarcinoma, clear cell renal carcinoma, neuroendocrine tumor, oncogenetic osteomalacia, sarcoma, CUP (cancer of unknown primary), thymic carcinoma, desmoid tumor, glioma, astrocytoma, cervical cancer, and prostate cancer.

[0301] In certain embodiments, the disease is selected from cardiovascular disease, liver fibrosis and cirrhosis, joint disorders (e.g., rheumatoid arthritis), IgG4-related disease, pulmonary fibrosis and interstitial lung disease, Crohn's disease, tuberculosis, sarcoidosis, and periprosthetic joint infections.

[0302] In another aspect of the present disclosure, a method for detecting a disease in a subject is provided, the method comprising administering to the subject an effective amount of a compound comprising a radionuclide as described herein or a pharmaceutical composition comprising the same, detecting localization of the radionuclide in the subject, for example using PET, PET-CT, or SPECT, and determining the presence or absence of the disease based on the presence or absence of localization. In some embodiments, the radionuclide is a metallic radionuclide. In certain embodiments, the radionuclide is 60 Cu, 61 Cu, 62 Cu, 64 Cu and 67 In some embodiments, the radionuclide is selected from Cu. 61 It is Cu.

[0303] In certain embodiments, the disease to be detected is any disease in which a FAP is overexpressed, such as cancer, inflammatory diseases, infectious diseases, and immune diseases.

[0304] In certain embodiments, the disease is cancer. In certain embodiments, the cancer is selected from breast cancer (e.g., triple-negative breast cancer), pancreatic cancer, small intestine cancer, colon cancer, gastric cancer, rectal cancer, lung cancer (e.g., non-small cell lung cancer), head and neck cancer, ovarian cancer, hepatocellular carcinoma, epithelial cancer, esophageal cancer, hypopharyngeal cancer, nasopharyngeal carcinoma, laryngeal cancer, myeloma cells, bladder cancer, cholangiocarcinoma, clear cell renal carcinoma, neuroendocrine tumor, oncogenetic osteomalacia, sarcoma, CUP (cancer of unknown primary), thymic carcinoma, desmoid tumor, glioma, astrocytoma, cervical cancer, and prostate cancer.

[0305] In certain embodiments, the disease is selected from cardiovascular disease, liver fibrosis and cirrhosis, joint disorders (e.g., rheumatoid arthritis), IgG4-related disease, pulmonary fibrosis and interstitial lung disease, Crohn's disease, tuberculosis, sarcoidosis, and periprosthetic joint infections.

[0306] Another aspect of the present disclosure provides a method for monitoring the effectiveness of cancer treatment in a subject suffering from cancer. The method includes administering to the subject an effective amount of a compound containing a radionuclide or a pharmaceutical composition containing the same as described herein, detecting the localization of the radionuclide in the subject using, for example, PET, PET-CT, or SPECT, and determining the effectiveness of the cancer treatment. In certain embodiments, a compound containing a radionuclide or a pharmaceutical composition containing the same is administered to the subject, and localization is observed at multiple time points, i.e., an earlier time point (e.g., before cancer treatment is initiated (t=0)) and a later time point, for example, 2 weeks after initiation of treatment, 3 weeks after initiation of treatment, 1 month after initiation of treatment, 2 months after initiation of treatment, 3 months after initiation of treatment, 4 months after initiation of treatment, 5 months after initiation of treatment, or 6 months or more after initiation of treatment. In certain, but not all, embodiments, the cancer treatment is determined to be beneficial (i.e., a positive effect) if less localization is observed at the later time point compared to the earlier time point. In certain, but not all, embodiments, a cancer treatment is determined to be not beneficial (i.e., adverse) if more localization is observed at later time points compared to earlier time points. In certain, but not all, embodiments, a cancer treatment is determined to be ineffective if there is no difference in localization at later time points compared to earlier time points.

[0307] 4.4.2. Treatment In one aspect of the disclosure, there is provided a method of treating a disease in a patient suffering from the disease, the treatment comprising administering to the patient an effective amount of a compound or pharmaceutical composition described herein.

[0308] In certain embodiments, the administered compound is a compound of Formula I, where T is not a radionuclide but includes a non-radionuclide-containing drug. Such embodiments are useful for treating inflammatory, infectious, and immune diseases. In certain embodiments, the disease is selected from cardiovascular disease, liver fibrosis and cirrhosis, joint disorders (e.g., rheumatoid arthritis), IgG4-related disease, pulmonary fibrosis and interstitial lung disease, Crohn's disease, tuberculosis, sarcoidosis, and periprosthetic joint infections.

[0309] In certain embodiments, the compound administered is a compound of Formula I, where T comprises a drug that is cytotoxic. 64 Cu and 67 Such embodiments include radionuclides selected from Cu. Such embodiments are useful in treating cancer, such as breast cancer (e.g., triple-negative breast cancer), pancreatic cancer, small intestine cancer, colon cancer, gastric cancer, rectal cancer, lung cancer (e.g., non-small cell lung cancer), head and neck cancer, ovarian cancer, hepatocellular carcinoma, epithelial carcinoma, esophageal cancer, hypopharyngeal cancer, nasopharyngeal carcinoma, laryngeal cancer, myeloma cells, bladder cancer, cholangiocarcinoma, clear cell renal carcinoma, neuroendocrine tumors, oncogene osteomalacia, sarcoma, CUP (cancer of unknown primary), thymic carcinoma, desmoid tumor, glioma, astrocytoma, cervical cancer, and prostate cancer.

[0310] Theranostics In one aspect of the present disclosure, theranostic methods, as provided herein, involve the use of pairs of Cu radiotracers ("theranostic pairs") for both imaging / diagnosis of disease and for treatment of disease in the same patient, where the theranostic pair of radiotracers differs only in the radionuclide, i.e., different radioisotopes. In certain embodiments, the theranostic pair includes a gamma- or positron-emitting radionuclide in the radiotracer for imaging / diagnosis (e.g., using PET, PET-CT, or SPECT) and a beta-emitting radionuclide in the radiotracer for treatment.

[0311] In certain embodiments, theranostic couples include: 61 Cu (imaging / diagnostic) and 67 Cu (therapeutic). In certain embodiments, 61 / 67 Called Cu Theranostic Vs.

[0312] Certain embodiments of theranostic methods involve the use of diagnostic forms of radiotracers (e.g., *Cu for PET). 61 Cu, or *Cu is the SPECT 67This involves the administration of a radiolabeled therapeutic target (Cu), allowing visualization of the expression of the therapeutic target in vivo using companion imaging techniques before switching to a radiolabeled therapeutic counterpart, e.g., *Cu 64 Cu or 67 It is Cu.

[0313] In certain embodiments, theranostic methods include: (a) As described herein 61 administering to a subject an effective amount of a compound containing a Cu radionuclide or a pharmaceutical composition containing the same; (b) generating one or more images of the subject (e.g., of a particular region or portion of the subject's body); (c) as described herein 67 administering to a subject an effective amount of a compound containing a Cu radionuclide or a pharmaceutical composition containing the same; Including, The compounds of steps (a) and (c) differ only in the identity of the radioisotope.

[0314] In certain embodiments, the compound described herein administered in step (a) 61 The amount of the compound containing a Cu radionuclide or pharmaceutical composition containing the same is effective to generate one or more images of the subject (i.e., a "detectably effective amount"). In certain embodiments, the amount of the compound or pharmaceutical composition containing the Cu radionuclide administered in step (a) described herein is effective to generate one or more images of the subject (i.e., a "detectably effective amount"). 61 The amount of the compound containing the Cu radionuclide or pharmaceutical composition containing same is effective for diagnosing the presence or absence of a disease (ie, a "diagnostically effective amount").

[0315] In certain embodiments, the method further comprises: acquiring, via one or more images of the subject, a body image of the subject; 61 and determining the presence or absence of a disease in the subject based on the presence or absence of localization of the Cu radionuclide. If the subject is not determined to have a disease, step (c) of the method is not performed.

[0316] In certain embodiments, the compound described herein administered in step (c) 67The amount of the compound containing the Cu radionuclide or pharmaceutical composition containing it is effective to treat the disease in question (ie, a "therapeutically effective amount").

[0317] In certain embodiments, theranostic methods include: (a) As described herein 61 generating one or more images of a subject (e.g., of a particular region or portion of the subject's body) comprising administering to the subject an effective amount of a compound comprising a Cu radionuclide or a pharmaceutical composition comprising the same; (b) on the subject's body via one or more images of the subject 61 determining the presence or absence of a disease in a subject based on the presence or absence of localization of Cu radionuclides; (c) if the presence of a disease in the subject is determined, 67 administering to the subject an effective amount of a compound containing a Cu radionuclide or a pharmaceutical composition containing the same, wherein the compounds of steps (a) and (c) differ only in the identity of the radionuclide. 5. List of embodiments Embodiment 1. A compound, wherein the compound is a compound of Formula I: [ka] R 1 is R a and; R 2 and R 3 are R a or together with the nitrogen atom to which they are attached and C 2-9 Forming a heterocyclic ring; R 4 is H, an amine protecting group, or -LT; R a independently for each occurrence, H, C 1-10 Alkyl, C 2-10 Alkenyl, C 3-10 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, C 2-9 Heterocyclyl, or C 5-9heteroaryl, optionally substituted with one or more substituents selected from —OH, —OR′, ═O, ═S, —SH, —SR′, —NH, —NHR′, —N(R′) , —NHCOR′, —NR′COR′, halogen, —CN, —COH, —COR′, —CHO, —COR′, —CONH, —CONHR′, —CON(R′) , —NO , —OP(O)(OH) , —SOH, —SOR′, —SOR′, and —SOR′; R′ is independently for each occurrence C 1-10 Alkyl or C 3-10 is cycloalkyl; L is a bond or a bivalent linker; T comprises (a) a chelating moiety suitable for chelating a radionuclide, (b) an imaging agent, or (c) a drug; n is an integer from 1 to 20; m is an integer from 1 to 20; or a pharmaceutically acceptable salt thereof. Embodiment 2.R 1 is methyl or H. Embodiment 3.R 2 is H and R 3 The compound of embodiment 1 or 2, wherein Embodiment 4.R 2 and R 3 together with the nitrogen atom to which they are attached and C 2-9 The compound of embodiment 1 or 2, which forms a heterocycle. Embodiment 5.C 2-9 The compound of embodiment 4, wherein the heterocycle is a 6-membered heterocycle selected from piperazine, hexahydropyrimidine, hexahydropyridazine, 1,2,3-triazinane, 1,2,4-triazinane, and 1,3,5-triazinane. Embodiment 6.R 4 The compound of any one of embodiments 1-5, wherein Embodiment 7.R 4 The compound of any one of embodiments 1-5, wherein is an amine protecting group. Embodiment 8.R 4The compound of any one of embodiments 1-5, wherein is -LT. Embodiment 9. The compound of embodiment 8, wherein L is a bivalent linker selected from an acid labile linker, a hydrolytically labile linker, an enzymatically cleavable linker, a reduction labile linker, a self-immolative linker, and a non-cleavable linker. Embodiment 10. The compound of embodiment 8 or 9, wherein T comprises a chelating moiety suitable for chelating a radionuclide. Embodiment 11. The compound of embodiment 10, wherein the chelating moiety is chelated to a radionuclide, and the radionuclide is selected from an alpha-emitting isotope, a beta-emitting isotope, a gamma-emitting isotope, an Auger electron-emitting isotope, an X-ray-emitting isotope, and a fluorescent-emitting isotope. Embodiment 12. The radionuclide is 225 Ac, 51 Cr, 66 Ga, 67 Ga, 68 Ga, [ 18 F]AlF, 111 In, 113m In, 52m Mn, 99m Tc, 186 Re, 188 Re, 139 La, 140 La, 175 Yb, 179 Yb, 153 Sm, 177m Sn, 166 Ho, 86 Y, 88 Y, 90 Y, 149 Pm, 165 Dy, 169 Er, 177 Lu, 52 Fe, 43 Sc, 44 Sc, 46 Sc, 47 Sc, 142 Pr, 157 Gd, 159 Gd, 212 Bi, 213 Bi, 72 As, 77 As, 97 Ru,109 Pd, 105 Rh, 101m Rh, 119 Sb, 197 Hg, 151 EU, 153 EU, 169 EU, 201 Tl, 149 Tb, 152 Tb, 155 Tb, 161 Tb, 203 Pb, 212 Pb, 151 Pm, 153 Pm, 142 Pr, 143 Pr, 55 Co, 60 Cu, 61 Cu, 62 Cu, 64 Cu, 67 Cu, 62 Zn, 188 Re, 198 Au, 199 Au, 227 Th, 111 Ag, 199 Ag, 211 At, 223 Ra, 88 Zr and 89 The compound of embodiment 11, wherein Zr is selected from Zr. Embodiment 13. The radionuclide is 61 Cu, 64 Cu and 67 The compound of embodiment 12, wherein the compound is selected from Cu. Embodiment 14. The chelating moiety is DOTAGA (1,4,7,10-tetraazacyclododecane, 1-(glutaric acid)-4,7,10-triacetic acid), DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid), DOTASA (1,4,7,10-tetraazacyclododecane-1-(2-succinic acid)-4,7,10-triacetic acid), CB-DO2A (10-bis(carboxymethyl)- 1,4,7,10-tetraazabicyclo[5.5.2]tetradecane), DEPA (7-[2-(bis-carboxymethylamino)-ethyl]-4,10-bis-carboxymethyl-1,4,7,10-tetraaza-cyclododec-1-yl-acetic acid)), 3p-C-DEPA (2-[(carboxymethyl)][5-(4-nitrophenyl-1-[4,7,10-tris(carboxymethyl)-1,4,7,10- Tetraazacyclododecan-1-yl]pentan-2-yl)amino]acetic acid), TCMC (2-(4-isothiocyanotobenzyl)-1,4,7,10-tetraaza-1,4,7,10-tetra-(2-carbamonylmethyl)-cyclododecane), oxo-DO3A (1-oxa-4,7,10-triazacyclododecane-5-S-(4-isothiocyanatobenzyl)-4,7,10-triacetic acid), p-NH2- Bn-oxo-DO3A (1-oxa-4,7,10-tetraazacyclododecane-5-S-(4-aminobenzyl)-4,7,10-triacetic acid), TE2A ((1,8-N,N'-bis-(carboxymethyl)-1,4,8,11-tetraazacyclotetradecane), MM-TE2A, DM-TE2A, CB-TE2A (4,11-bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane), CB-TE1A1P (4,8,11-tetraazacyclotetradecane-1-(methanephosphonic acid)-8-(methanecarboxylic acid), CB-TE2P (1,4,8,11-tetraazacyclotetradecane-1,8-bis(methanephosphonic acid), TETA (1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid), NOTA (1,4,7-triazacyclononane-N,N',N"-triacetic acid), NODA (1,4, 7-triazacyclononane-1,4-diacetate), NODAGA (1,4,7-triazacyclononane-1-glutaric-4,7-acetic acid) (also known as NOTAGA), NODA deferoxamine (1,4,7-triazacyclononane-1,4-diyl)diacetic acid DFO), NETA ([4-[2-(bis-carboxymethylamino)-ethyl]-7-carboxymethyl-[1,4,7]triazonan-1-yl}acetic acid), TACN-TM (N ,N',N”,tris(2-mercaptoethyl)-1,4,7-triazacyclononane), Diamsar (1,8-diamino-3,6,10,13,16,19-hexazabicyclo(6,6,6)eicosane, 3,6,10,13,16,19-hexazabicyclo[6.6.6]eicosane-1,8-diamine), Sarar (1-N-(4-aminobenzyl)-3,6,10,13,16,19-hexazabicyclo[6.6.6]eicosane- 14. The compound of any one of embodiments 10 to 13, wherein the compound is selected from AmBaSar (4-((8-amino-3,6,10,13,16,19-hexazabicyclo[6.6.6]icosan-1-ylamino)methyl)benzoic acid), AmBaSar (4-((8-amino-3,6,10,13,16,19-hexazabicyclo[6.6.6]icosan-1-ylamino)methyl)benzoic acid), and 4,4'-((3,6,10,13,16,19-hexazabicyclo[6.6.6]ico-san-1,8-diylbis(aza-nediyl))bis(methylene))dibenzoic acid (BaBaSar). Embodiment 15. The compound of embodiment 8 or 9, wherein T comprises an imaging agent, and the imaging agent comprises a radionuclide or a fluorescent dye. Embodiment 16: The compound of embodiment 8 or 9, wherein T comprises a drug, and the drug comprises a chelating moiety chelated to a radionuclide. Embodiment 17: The compound of embodiment 1, wherein the compound is a compound of formula Ia or formula (Ib): [ka] Embodiment 18.R 1 is H or methyl. Embodiment 19.R 4 The compound of embodiment 17 or 18, wherein is -LT. Embodiment 20. T comprises a chelating moiety chelated to a radionuclide, wherein the chelating moiety is selected from DOTAGA, DOTA, NOTA, NODAGA, and NODA; Radionuclides are 61 Cu, 64 Cu and 67 Cu, A compound according to any one of embodiments 17 to 19. Embodiment 21. The compound is [Table 4-1] [Table 4-2] [Table 4-3] or a pharmaceutically acceptable salt thereof, and *Cu is 61 Cu, 62 Cu, 64 Cu and 67 Cu, especially 61 Cu and 67 The compound of embodiment 1, selected from Cu. Embodiment 22. A pharmaceutical composition comprising a compound according to any one of embodiments 1 to 21 and a pharmaceutically acceptable excipient. Embodiment 23.R 423. The pharmaceutical composition of embodiment 22, wherein: is -LT, and the composition is characterized by one or more of: (i) a molar radioactivity of 3 MBq / nmol or greater; (ii) a radiochemical purity of 91% or greater; (iii) a radioactivity concentration of 8 MBq / mL or greater; and (iv) a radionuclide purity of the compound at the end of synthesis (EoB+2 hours) of 95% or greater. Embodiment 24. A method for generating one or more images of an object, comprising: Radionuclides 61 administering to a subject an effective amount of a compound of embodiment 13, wherein the compound is Cu; generating one or more images of at least a portion of a subject's body; A method comprising: Embodiment 25. The method of embodiment 24, wherein the image is generated using positron emission tomography (PET), PET-computed tomography (PET-CT), or single-photon emission computed tomography (SPECT). Embodiment 26. A method of treating a disease in a patient in need thereof, comprising administering to the patient an effective amount of a compound of any one of embodiments 1-14, or 16-20. Embodiment 27. The method of embodiment 26, wherein the disease is selected from cancer, an inflammatory disease, an infectious disease, and an immune disease. Embodiment 28. A theranostic method, comprising: (a) Radionuclides 61 an effective amount of the first compound of embodiment 13, wherein the radionuclide is Cu; 61 administering to the subject a pharmaceutical composition comprising an effective amount of the first compound of embodiment 13, wherein the first compound is Cu; (b) generating one or more images of the object; (c) Radionuclides 67 an effective amount of the second compound of embodiment 13, wherein the radionuclide is Cu; 67 Administering to a subject a pharmaceutical composition comprising an effective amount of a second compound of embodiment 13, wherein the first and second compounds of step (a) and step (c) differ only in the identity of the radioisotope. A method comprising: Embodiment 29. (a) The first compound is 61 [Cu]Cu-NODAGA-1, and the second compound 67 [Cu]Cu-NODAGA-1; (b) the first compound is 61 [Cu]Cu-NODAGA-2, and the second compound 67 [Cu]Cu-NODAGA-2; (c) the first compound is 61 [Cu]Cu-NODAGA-3, and the second compound 67 [Cu]Cu-NODAGA-3; or (d) the first compound is 61 [Cu]Cu-NODAGA-4, and the second compound 67 [Cu]Cu-NODAGA-4, 29. The method of embodiment 28. Embodiment 30. Intracellular administration of a first compound in the body of a subject. 61 30. The method of embodiment 28 or 29, further comprising determining the presence or absence of disease in the subject via one or more images of the subject based on the presence or absence of localization of the Cu radionuclide.

[0318] 6. Example Example 1: Synthesis of FAP inhibitors 1.1: Synthesis of (S)-N1-(2-aminoethyl)-N4-(4-((2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)succinimide (1) Step 1: (S)-6-amino-N-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)quinoline-4-carboxamide (A) [ka]

[0319] The two precursors (purchased from AstaTech) were dissolved in DMF along with HATU, followed by the addition of DCM. DIPEA was added dropwise, and the reaction was monitored by LC / MS. The reaction was complete in less than 1 h. The crude product was concentrated, diluted with water / ACN 85:15, and directly purified by HPLC (LCMS-2020 Shimadzu system equipped with a Gemini C-6 Phenyl column (10 × 250 mm, 5 μm particle size)). The gradient used was 5–80% solvent B in 15 min (A = HO [0.1% TFA], B = ACN [0.1% TFA]), flow rate 5.0 mL / min), affording A as a pure red powder (38 mg, 84% yield).

[0320] Step 2: Synthesis of (S)-4-((4-((2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)amino)-4-oxobutanoic acid (B) [ka]

[0321] (S)-6-amino-N-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)quinoline-4-carboxamide (A) and succinic anhydride were dissolved in THF. DIPEA was added dropwise, and the reaction was mixed overnight and confirmed by LC / MS. The crude product was directly purified by HPLC (LCMS-2020 Shimadzu system equipped with a Gemini C-6 Phenyl column (10 × 250 mm, 5 μm particle size)). The gradient used was 5–80% solvent B in 8 min (A = HO [0.1% TFA], B = ACN [0.1% TFA]), flow rate 5.0 mL / min), affording B as a yellow powder (32.7 mg, 68% yield).

[0322] Step 3: (S)—N1-(2-aminoethyl)-N4-(4-((2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)succinimide (1) [ka]

[0323] S)-4-((4-((2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)amino)-4-oxobutanoic acid (B), HATU, and the amine were dissolved in DCM and DMF. DIPEA was added dropwise, and the reaction was mixed and checked by LC / MS. After completion, TIPS was added and TFA was added dropwise: first, DIPEA was quenched. The deprotection step was complete in 2 days. The crude material was used without further purification.

[0324] 1.2: Synthesis of (S)-N1-(2-aminoethyl)-N4-(4-((2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)-N4-methylsuccinamide (2) Compound 2 was prepared as shown in Scheme 1: Scheme 1 [ka]

[0325] Step 1: To a mixture of compound A (4.17 g, 22.2 mmol) in MeOH (84.0 mL) was added SOCl2 (26.4 g, 222 mmol, 16.1 mL) in one portion at 0-5 °C under N2. The reaction was stirred at 0-5 °C for 0.5 h. The mixture was heated to 75 °C and stirred for 12 h. SOCl2 (26.4 g, 222 mmol, 16.1 mL) was added to the mixture and stirred at 75 °C for 12 h. SOCl2 (26.4 g, 222 mmol, 16.1 mL) was added to the mixture and stirred at 75 °C for 12 h. SOCl2 (13.2 g, 111 mmol, 8.04 mL) was added to the mixture and stirred at 75 °C for 12 h. LC-MS showed that one major peak with the desired mass was detected. The mixture was concentrated in vacuo. The crude product was triturated with MeCN (300 mL) at 20° C. for 1 h to give compound B (7.05 g, crude) as a brown solid. 1H NMR: (400 MHz, DMSO-d) δ 8.81 (d, J = 4.8 Hz, 1H), 8.27 (d, J = 8.8 Hz, 1H), 8.10 (d, J = 4.8 Hz, 1H), 7.82 (s, 1H), 7.67 (d, J = 8.0 Hz, 1H), 3.98 (s, 3H). LC-MS (LCMS-2020 Shimadzu system equipped with a Gemini C-6 Phenyl column (3.5 × 250 mm, 5 µm particle size). The gradient used was 5–80% solvent B in 8 min (A = HO [0.1% TFA], B = ACN [0.1% TFA]), flow rate 1.0 mL / min, product: RT = 1.262 min).

[0326] Step 2: To solution B (7.02 g, 34.7 mmol) in MeOH (100 mL) and BocO (100 mL) was added TEA (7.03 g, 69.4 mmol), and the mixture was stirred at 25 °C for 12 h. LCMS showed that compound B was consumed, with one peak of the desired MS signal detected. The mixture was concentrated in vacuo. Column chromatography (SiO, petroleum ether / ethyl acetate = 100 / 1 to 1 / 1) was used to eluate compound CR. f =0.35) to give compound C (4.36 g, yield 41.5%) as a brown solid. 1 H NMR:(400MHz,CDCl3)δ 8.89(d,J=4.4Hz,1H),8.78(d,J=2.4Hz,1H),8.11(d,J=9.2Hz,1H),7.96-7.89(m,2H),6.83(s,1H),4.04(s,3H),1.57(s,9H).

[0327] Step 3: To a solution of compound C (3.36 g, 11.1 mmol) in DMF (84.0 mL), NaH (778 mg, 19.5 mmol, 60% purity) was added portionwise at 0 °C, and the mixture was stirred at 25 °C for 20 min. MeI (3.94 g, 27.8 mmol) was added to the reaction mixture at 25 °C, and the mixture was stirred at 25 °C for 2 h. LCMS (ET60385-17-P1A3, product RT = 0.562 min) showed that compound C was consumed, and one peak of the desired MS was detected. The reaction mixture was cooled to 0 °C, quenched with brine (80.0 mL), and extracted with EtOAc (3 × 100 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to give compound D (4.78 g, crude) as a brown solid.

[0328] Step 4: To a solution of compound D (4.78 g, 15.1 mmol) in DCM (50.0 mL), TFA (8.61 g, 75.5 mmol) was added dropwise, and the mixture was stirred at 25 °C for 12 h. LCMS showed that compound D was consumed, with one peak of the desired MS signal being detected. The reaction mixture was quenched with saturated NaHCO (50.0 mL) and extracted with DCM (3 × 40.0 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. Column chromatography (SiO, petroleum ether / ethyl acetate = 100 / 1 to 1 / 1) afforded product R. f =0.40) to obtain compound E (2.51 g, yield 76.8%) as a brown solid. 1 H NMR:ET60385-19-P1A1(400MHz,CDCl3)δ 8.67(d,J=4.4Hz,1H),7.94(d,J=9.2Hz,1H),7.85(d,J=4.4Hz,1H),7.80(d,J=2.4Hz,1H),7.17-7.14(m,1H),4.02(s,3H),3.01(s,3H).

[0329] Step 5: To a solution of compound E (500 mg, 2.31 mmol) in THF (4.00 mL), tetrahydrofuran-2,5-dione (231 mg, 2.31 mmol) was added, and the reaction mixture was stirred at 50° C. for 12 hours. LCMS showed that compound E was consumed, and one peak of the desired MS was detected. The mixture was concentrated in vacuo to give compound F (716 mg, crude) as a brown solid. 1 H NMR:ET60385-43-P1A1(400MHz,CDCl3)δ 9.10(d,J=4.0Hz,1H),8.77(d,J=2.4Hz,1H),8.28(d,J=8.8Hz,1H),8.03(d,J=4.0Hz,1 H),7.66-7.64(m,1H),4.06(s,3H),3.42(s,3H),2.69-2.66(m,2H),2.51-2.50(m,2H).

[0330] Step 6: To a solution of compound F (716 mg, 2.26 mmol) in DMF (7.00 mL), TEA (343 mg, 3.40 mmol), HOBt (458 mg, 3.40 mmol), EDCI (650 mg, 3.40 mmol), and tert-butyl N-(2-aminoethyl)carbamate (398 mg, 2.49 mmol) were added, and the reaction mixture was stirred at 25 °C for 12 hours. LCMS showed that compound F was consumed, and one peak of the desired MS was detected. The reaction mixture was quenched with saturated NaHCO (15.0 mL), extracted with DCM (25.0 mL × 3), and washed with brine (15.0 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to give compound G (1.33 g, crude) as a brown solid.

[0331] Step 7: To a solution of compound G (1.33 g, 2.90 mmol) in Py (20.0 mL) was added LiI (7.86 g, 58.6 mmol), and the mixture was stirred at 110 °C for 4 hours. LCMS showed that compound G was consumed, with one peak of the desired MS. The mixture was concentrated in vacuo. The residue was purified by preparative HPLC (column: Welch Xtimate C18 250*100 mm#10 um; mobile phase: [water (NH4HCO3)-ACN]; B%: 1% to 30%, 20 min) to give compound H (647 mg, 50.1% yield) as an off-white solid.

[0332] Step 8: To a solution of compound H (617 mg, 1.39 mmol) in DMF (6.00 mL), DIEA (717 mg, 5.55 mmol), HATU (791 mg, 2.08 mmol), and compound 6-1 (587 mg, 2.08 mmol, 80% purity, HCl) were added, and the mixture was stirred at 25 °C for 1 hour. LCMS showed that compound H was consumed, and one peak of the desired MS was detected. The reaction mixture was quenched with saturated NaHCO (15.0 mL), extracted with DCM (25.0 mL × 3), and washed with brine (15.0 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to give compound I (2.70 g, crude) as a brown solid.

[0333] Step 9: To a solution of compound I (2.70 g, 4.39 mmol) in DCM (10.0 mL), TFA (41.5 g, 364 mmol) was added, and the mixture was stirred at 25 °C for 1 h. LCMS (ET60385-61-P1A4, product RT = 0.490 min) showed that compound I was consumed, and one peak of the desired MS was detected. The mixture was concentrated in vacuo. The residue was purified by preparative HPLC (column: Welch Xtimate C18 250*100 mm#10 um; mobile phase: [water (NH4HCO3)-ACN]; B%: 5% to 35%, 20 min) to give compound 2 (260 mg, 11.1% yield, 97.3% purity) as a brown solid. LCMS (LCMS-2020 Shimadzu system equipped with a Gemini C-6 Phenyl column (3.5 × 250 mm, 5 μm particle size). The gradient used was 5–80% solvent B in 8 min (A = HO [0.1% TFA], B = ACN [0.1% TFA]), flow rate 1.0 mL / min, product RT = 0.493 min).

[0334] 1.3: Synthesis of (S)-N-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)-6-(4-oxo-4-(piperazin-1-yl)butanamido)quinoline-4-carboxamide (3) [ka] (S)-4-((4-((2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)amino)-4-oxobutanoic acid, HATU, and the amine were dissolved in DCM and DMF. DIPEA was added dropwise to check the reaction. When all coupling had occurred, the crude product was concentrated slightly, then TIPS was added. TFA was added dropwise, and the mixture was checked by LC / MS until completion. The crude product (3) was used directly.

[0335] 1.4: Synthesis of (S)-N-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)-6-(N-methyl-4-oxo-4-(piperazin-1-yl)butanamido)quinoline-4-carboxamide (4) Compound 4 was prepared as shown in Scheme 2: Scheme 2 [ka]

[0336] Step 1: To a mixture of compound J (10.0 g, 53.7 mmol) in DCM (70.0 mL) was added tetrahydrofuran-2,5-dione (5.37 g, 53.7 mmol). The mixture was stirred at 20° C. for 2 hours. TLC (dichloromethane / methanol / AcOH=9 / 1 / 0.01) showed that compound JR f =0.0) indicated that the reaction was complete. The mixture was concentrated in vacuo. The residue was purified by silica gel chromatography (dichloromethane / methanol = 100 / 1, 9 / 1) to give compound K (4.75 g, yield 30.9%) as a white solid. 1 H NMR:(400MHz,CDCl3)δ 10.56-11.09(m,1H),3.53-3.62(m,2H),3.45(s,4H),3.36-3.42(m,2H),2.60-2.73(m,4H),1.45(s,9H).

[0337] Step 2: To a solution of compound L (300 mg, 1.39 mmol) in EtOAc (10.0 mL), DIEA (537 mg, 4.16 mmol), compound K (476 mg, 1.66 mmol), and T3P (11.2 g, 17.7 mmol, 50% purity) were added, and the reaction mixture was stirred at 25 °C for 0.5 h. LCMS showed that compound L was consumed, with one peak of the desired MS. The reaction mixture was then diluted with EtOAc (20.0 mL) and washed with water (60.0 mL), saturated NaHCO3 (60.0 mL), and brine (20.0 mL). The organic phase was dried over Na2SO4 and concentrated in vacuo to give compound M (716 mg, crude) as a brown oil.

[0338] Step 3: To a solution of compound M (716 mg, 1.48 mmol) in Py (20.0 mL), LiI (3.96 g, 29.5 mmol) was added, and the mixture was stirred at 110 °C for 4 hours. LCMS showed that compound M was consumed, with one peak of the desired MS. The mixture was concentrated in vacuo. The residue was purified by preparative HPLC (column: Welch Xtimate C18 250*100 mm#10 um; mobile phase: [water (NH4HCO3)-ACN]; B%: 1% to 30%, 20 min) to give compound N (460 mg, 64.4% yield, 97.4% purity) as an off-white solid. LCMS (LCMS-2020 Shimadzu system equipped with a Gemini C-6 Phenyl column (3.5 × 250 mm, 5 μm particle size). The gradient used was 5–80% solvent B in 8 min (A = HO [0.1% TFA], B = ACN [0.1% TFA]), flow rate 1.0 mL / min, product RT = 0.596 min).

[0339] Step 4: To a solution of compound N (460 mg, 977 μmol) in DMF (5.00 mL), DIEA (505 mg, 3.91 mmol), PYBOP (763 mg, 1.47 mmol), and compound 6-1 (330 mg, 1.47 mmol, HCl) were added, and the mixture was stirred at 25 °C for 1 h. LCMS showed that one peak of the desired MS was detected. The reaction mixture was quenched with saturated NaHCO (15.0 mL), extracted with DCM (25.0 mL × 3), and washed with brine (15.0 mL). The organic layer was dried over NaSO, filtered, and concentrated in vacuo to give compound O (2.10 g, crude) as a brown oil.

[0340] Step 5: To a solution of compound O (2.10 g, 3.27 mmol) in DCM (10.0 mL), TFA (15.4 g, 135 mmol) was added, and the mixture was stirred at 25 °C for 1 hour. LCMS showed that compound O was consumed, and one peak of the desired MS was detected. The mixture was concentrated in vacuo. The residue was purified by preparative HPLC (column: Welch Xtimate C18 250*70 mm#10 um; mobile phase: [water (NH4HCO3)-ACN]; B%: 0% to 40%, 20 min) to give compound 4 (196 mg, 11.0% yield) as an off-white solid.

[0341] 1.5: Synthesis of FAPI-46 FAPI-46 was prepared as shown in Scheme 3: Scheme 3 [ka]

[0342] FAPI-46 can also be prepared according to the methods described in WO 2019 / 154886.

[0343] Example 2: Synthesis of FAPI-NODAGA conjugate 2.1: Synthesis of 2,2'-(7-((R)-1-carboxy-4-((2-(4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)amino)-4-oxobutanamido)ethyl)amino)-4-oxobutyl)-1,4,7-triazonane-1,4-diyl)diacetic acid ((R)-NODAGA-1) [ka] To the crude (S)-N1-(2-aminoethyl)-N4-(4-((2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)succinimide (1) solution, DIPEA was added dropwise to neutralize the TFA. HATU and NODAGA-Tris(tBu) were then added dropwise as a DMSO solution (150 μL). The reaction was complete after a few minutes. The crude product was concentrated and purified via HPLC. To the pure material, DCM, TIPS, and TFA were added, and the reaction was left to complete for 1 day. Purification via HPLC afforded 15.8 mg of (R)-NODAGA-1 as a pale yellow powder (yield: 51%).

[0344] 2.2: Synthesis of 2,2'-(7-((R)-1-carboxy-4-((2-(4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)(methyl)amino)-4-oxobutanamido)ethyl)amino)-4-oxobutyl)-1,4,7-triazonane-1,4-diyl)diacetic acid ((R)-NODAGA-2) [ka] Step 1: To a solution of compound 2 (80.0 mg, 155 μmol) in DMF (1.00 mL), DIEA (80.2 mg, 620 μmol), HATU (121 mg, 232 μmol), and NODAGA-Tris(tBu) (101 mg, 186 μmol) were added, and the mixture was stirred at 25 °C for 1 h. LCMS showed that compound 2 was consumed, with one peak of the desired MS signal being detected. The reaction mixture was quenched with saturated NaHCO (4.00 mL), extracted with DCM (10.0 mL × 3), and washed with brine (10.0 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to give R (310 mg, crude) as a brown oil.

[0345] Step 2: To a solution of compound R (310 mg, 297 μmol) in TFA (1.29 g, 11.3 mmol) at 25 °C, the mixture was stirred at 25 °C for 1 h. LCMS showed that compound R was consumed, and one peak of the desired MS was detected. The mixture was concentrated in vacuo. The crude products ET60385-73 (220 mg, crude) and ET60385-78 (206 mg, crude) were combined for further purification. The residue was purified by preparative HPLC (column: C18-1 150*30 mm*5 μm; mobile phase: [water (TFA)-ACN]; B%: 5% to 35%, 20 min) to give (R)-NODAGA-2 (10.01 mg, yield 3.30%, purity 96.9%, TFA) as a brown solid. 1 H NMR:ET60385-73-P1A2(400MHz,D2O)δ 9.14(d,J=5.2Hz,1H),8.32-9.30(m,2H),8.02-7.98(m,2H),5.18-5.14(m ,1H),4.38(s,2H),4.33-4.24(m,1H),4.20-4.10(m,1H),3.76(s,4H),3.51 -3.31(m,4H),3.25-3.12(m,12H),3.03-2.87(m,6H),2.49(s,3H),2.30(t ,J=7.2Hz,2H),2.03-1.85(m,1H).LCMS(ET60385-73-P1Z1, product RT=1.610 minutes).

[0346] 2.3: Synthesis of 2,2'-(7-((R)-1-carboxy-4-(4-(4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)amino)-4-oxobutanoyl)piperazin-1-yl)-4-oxobutyl)-1,4,7-triazonane-1,4-diyl)diacetic acid ((R)-NODAGA-3) [ka] To the crude (S)-N-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)-6-(4-oxo-4-(piperazin-1-yl)butanamido)quinoline-4-carboxamide solution, DIPEA was added dropwise to neutralize the TFA. HaTU and NODAGA-Tris(tBu) were then added dropwise as a DMSO solution (150 μL). The reaction was complete after a few minutes. The crude product was concentrated and purified via HPLC. To the pure material, DCM, TIPS, and TFA were added, and the reaction was left to complete for 1 day. Purification via HPLC afforded 15.8 mg of (R)-NODAGA-3 as a pale yellow powder (yield: 26%).

[0347] 2.4: Synthesis of 2,2'-(7-((R)-1-carboxy-4-(4-(4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)(methyl)amino)-4-oxobutanoyl)piperazin-1-yl)-4-oxobutyl)-1,4,7-triazonane-1,4-diyl)diacetic acid ((R)-NODAGA-4) [ka] Step 1: To a solution of compound 4 (40.0 mg, 73.8 μmol) in DMF (0.50 mL), DIEA (9.55 mg, 73.8 μmol), HATU (57.6 mg, 110 μmol), and NODAGA-Tris(tBu) (48.1 mg, 88.6 μmol) were added. The mixture was stirred at 25 °C for 1 hour. LCMS showed that one peak of the desired MS was detected. The mixture was concentrated in vacuo. The residue was purified by preparative HPLC (column: Waters Xbridge Prep OBD C18 150*40 mm*10 μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 50%-90%, 8 min) to give compound S (28.0 mg, 35.5% yield) as a white solid.

[0348] Step 2: Compound S (28.0 mg, 26.2 μmol) was placed in a microwave tube in HFIP (4.41 mg, 26.2 μmol). The sealed tube was heated in a microwave at 100 °C for 48 hours. LCMS showed that compound S was consumed, with one peak of the desired MS. The mixture was concentrated in vacuo. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 75*30 mm*3 μm; mobile phase: [water (TFA)-ACN]; B%: 5% to 30%, 8 min) to give (R)-NODAGA-4 (9.01 mg, 36.9% yield, 96.6% purity, TFA) as an off-white solid. 1 H NMR: (400 MHz, DO) δ 9.10 (d, J = 4.8 Hz, 1H), 8.31-8.27 (m, 2H), 8.00-7.97 (m, 2H), 5.15-5.12 (m, 1H), 4.35 (s, 2H), 4.26-4.22 (m, 1H), 4.17-4.15 (m, 1H), 3.75 (s, 4H), 3.60-3.50 (m, 9H), 3.22-3.09 (m, 18H), 2.67-2.58 (m, 6H), 2.07-1.96 (m, 2H). LCMS (LCMS-2020 equipped with a Gemini C-6 Phenyl column (3.5 x 250 mm, 5 μm particle size)) Shimadzu system. The gradient used was 5–80% solvent B in 8 min (A = HO [0.1% TFA], B = ACN [0.1% TFA]), flow rate 1.0 mL / min, product RT = 1.640 min).

[0349] 2.5: Synthesis of 2,2'-(7-(1-carboxy-4-(4-(3-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)(methyl)amino)propyl)piperazin-1-yl)-4-oxobutyl)-1,4,7-triazonane-1,4-diyl)diacetic acid (NODAGA-FAPI-46) [ka] (S)-N-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)-6-(4-oxo-4-(piperazin-1-yl)butanamide)quinoline-4-carboxamide, (R)-NODAGA(tris)tBu, and HATU were dissolved in DCM + 100 μL of DMF. DIPEA was added dropwise, and the reaction was stirred for 2 h until complete (confirmed via LC / MS, 15-80% in ACN). When no starting material remained and only a peak related to the product mass was observable (m / z = 1025), TIPS and TFA (600 μL) were added. After 48 h, the reaction was complete. The crude product was purified by HPLC (10-65% CAN in 15 min, rt = 9.5) to give 6.8 mg of a red powder (yield: 36%).

[0350] Example 3: Cold labeling nat Cu-NODAGA-1 and nat Cu-NODAGA-3 nat The Cu complexes were prepared by dissolving each conjugate in ammonium acetate buffer, 0.5 M, pH 8, with a 1.5-fold excess of nat It was prepared by incubating with CuCl2x 2 H2O at 95°C for 15 minutes. nat Cu ions were removed by SepPak C-18 purification. nat The Cu complexes were eluted with methanol, evaporated to dryness, redissolved in water, and lyophilized. The purity of all complexes was confirmed by liquid chromatography and mass spectrometry (LC-MS). Table 1 shows the retention time (t R ), and ion [M+2H] compared to the theoretical mass 2+ The resulting mass (mass-to-charge ratio, m / z) of the formed nat The identity of the Cu-complexed conjugate was confirmed. Analysis was performed on an LC-MS (Shimadzu LC2020) system using a Gemini C6 Phenyl 5 μm, 250 x 4.6 mm column and a gradient of 15 to 80% acetonitrile (0.1% TFA) / water (0.1% TFA) for 15 min at a flow rate of 2 mL / min. LC-MS chromatogram data are provided in Table 1A. [Table 5]

[0351] nat Cu-NODAGA-2 and nat Cu-NODAGA-4 by incubating 1–1.5 mg of each conjugate with a 1.5-fold excess of CuCl2 in 125–300 μL of ammonium acetate (0.5 M, pH 8). nat The Cu complex was prepared. A pH check was performed to ensure the necessary conditions for the reaction (pH ≥ 5). The reaction mixture was incubated at room temperature for 10 min. Free metal ions were removed via HPLC (Shimadzu SCL-40, Phenomenex Jupiter Proteo C12 (90 Å, 250 × 4.6 mm) column using a gradient of 15–80% B over 8 min (A = HO [0.1% TFA], B = ACN [0.1% TFA]) at a flow rate of 5 mL / min. [Table 6]

[0352] Example 4: High purity copper-61 ( 61 Cu) 1. Coin manufacturing method Preparation of buffer solutions Ammonium chloride (4.6 g, Aldrich: 326372, Trace Select) was weighed into a clean (metal-free) Falcon tube (50 mL) and a previously cleaned magnetic stir bar was added. If salt adhered to the walls of the Falcon tube, 6 mL of Trace Select water (Honeywell 95305) was added at once to wash the walls of the Falcon tube. 1 mL of 28% ammonium hydroxide (Sigma 338818) was added eight times using a 1000 μL pipette with the appropriate pipette tip. The Falcon lid was closed, and the Falcon was vortexed (1–2 min) and shaken in sequence until all salt was dissolved (immersion in an ultrasonic bath for 1–2 min was a possible alternative). The Falcon tube could also be warmed (e.g., by rolling it between hands) to improve solubility. Temperature (e.g., approximately 23°C, preferably 23–25°C) was used. After the salt was completely dissolved, the pH acceptance criteria, pH range 9.28-9.62, was verified by measuring the pH of the solution at room temperature, e.g., with an electronic pH meter. The Falcon tube was closed with parafilm and stored at room temperature. Any solid salt formers were redissolved before use.

[0353] Preparation of nickel nitrate plating solution A 50 mL glass beaker was rinsed with nitric acid (Trace Select) followed by water (Trace Select). The beaker was placed on a heating plate set at 150 °C in a fume hood to dry. 210 mg of natural (isotopic distribution) nickel (powder, Sigma-Aldrich, <50 μm, 99.7% trace metals standard, essentially free of any impurities except iron; copper impurity <0.3 ppm) was weighed into the beaker, and 4 mL of 65% nitric acid was added using a pipette. The beaker was placed back on the active heating plate, and stirring was set to 300 rpm. Proper ventilation of the fume hood was confirmed (NO2 evolution). During dissolution, the solution turned green. The solution was reduced to a volume of approximately 600 μL by evaporation, removed from the heating plate, and allowed to cool to room temperature. The remaining solution was transferred to a 50 mL metal-free Falcon tube. The glass beaker was rinsed with 2.8 mL of Trace Select water in 0.8 mL, 1 mL, and 1 mL steps, and each step was transferred to a Falcon tube before the next wash fraction was added. Buffer solution (4 mL), 11 mL of Trace Select water, and 3 mL of ammonium hydroxide 28% (Sigma 338818) were added to the Falcon tube. The pH of the solution was measured and adjusted to the required pH by adding ammonium hydroxide 28% (Aldrich 338818) using a sterile B-Braun syringe.

[0354] 60 Ni and 61 Examples of suitable starting materials for preparing Ni electroplating solutions Tables 2 to 4 below are 60 Ni and 61 An example of a Ni lot (certificate provided by Isoflex, USA, March 2018): [Table 7] [Table 8] [Table 9]

[0355] The sample of natural nickel from Sigma-Aldrich was essentially free of any impurities except iron. Copper impurities amount to <0.3 ppm. The Certificate of Analysis is provided below. Further suitable sources of natural Ni include: Nickel powder, <50μm, 99.7% trace metals basis Nickel rod, diameter 6.35mm, =99.99% trace metals basis Nickel foil, 0.5mm thick, 99.98% trace metals

[0356] Preparation of zinc nitrate plating solution A 50 mL glass beaker was washed with nitric acid (Trace Select) followed by water (Trace Select). In a fume hood, the beaker was placed on a heating plate set at 150 °C to dry. 210 mg of natural (isotope-distributed) zinc (zinc powder, Sigma-Aldrich, <10 μm, >98%) was weighed into the beaker, and 4 mL of 65% nitric acid was added using a pipette. The beaker was placed back on the active heating plate, and stirring was set to 300 rpm. Proper ventilation of the fume hood was confirmed (NO2 evolution). During dissolution, the solution turned green. The solution was reduced to a volume of approximately 600 μL by evaporation, removed from the heating plate, and allowed to cool to room temperature. The remaining solution was transferred to a 50 mL metal-free falcon tube. The glass beaker was rinsed with 2.8 mL of Trace Select water in 0.8 mL, 1 mL, and 1 mL steps, each of which was transferred to a falcon tube before the next wash fraction was added. 4 mL of buffer (prepared above), 11 mL of Trace Select water, and 3 mL of ammonium hydroxide 28% (Sigma 338818) were added to a Falcon tube. The pH of the solution was measured and adjusted to the required pH by adding ammonium hydroxide 28% (Aldrich 338818) using a sterile B-Braun syringe.

[0357] Electroplating of backing surface A niobium backing disk (28 mm x 1.0 mm) was obtained from the high-purity Nb described herein. It was washed with ethanol (high purity) and inserted into a Comecer V21204 electroplating unit. A platinum wire anode was positioned approximately 1–3 mm from the coin surface using a polymer spacer. The coin mass was determined to be 5.25 grams. The niobium backing (22 mm x 1.0 mm, weighing 3.3 g) was used. The plating solution was added to the electrolyte reservoir and attached to the device. The voltage was set to 4.5 V. After 5 minutes of stabilization, the measured current was 180 μA. The pump duty cycle was set to 45%. The plating solution changed from blue to clear, and a gradual current decrease to 160 μA was observed over 120 minutes. The plating process was stopped. The coin was removed from the electrolytic cell and weighed. Microscopic evaluation of the coin was also performed using a DINOLite digital microscope to observe the surface crystalline structure and uniformity (Figure 16). The coins (Figure 17) were stored in metal-free Falcon tubes under a nitrogen atmosphere.

[0358] After electroplating was completed, the coins were subjected to microscopic evaluation using a DINOLite digital microscope to observe the crystalline structure and uniformity of the surface. As can be seen in Figure 16 (panels A-C), a homogeneous target coating with lasting adhesion was obtained.

[0359] 2.High purity [ 61 General guidelines for Cu]Cl2 production The purpose of this example is to identify natural nickel and / or enriched nickel. 60 Deuteron irradiation of Ni to copper-61( 61 The goal of this work was to enable mass production of ZnO (Cu). This work was a proof of concept and therefore 61 There was no benchmark specification for Cu. However, the inventors 60 After Ni irradiation, 61 Cu] to generate CuCl2, or natOptimize target performance, target geometry / material use, irradiation parameters, and chemical processing methods to scale for Ni irradiation. While no clear pharmacopoeial specifications exist for radioactive copper, test QC methods were developed based on the extracted [ 61 Cu]CuCl2) including assessment of radionuclide purity and apparent molar activity.

[0360] In this example, two different types of targets, natural nickel ( nat Ni) target and highly enriched nickel-60 ( 60 Ni) targets, both of which were suitable for deuteron bombardment, except that nat Ni was cost-effective and available in high purity, 60 Ni remains expensive and requires efficient means. If even higher yields are desired, target preparation efforts should focus on proton-based 61 Ni(p,n) 61 Although it can be directly converted to Cu pathway, enrichment 61 Considering the cost of Ni (approximately US$25 / mg), such an approach imposes the need for targeted recycling.

[0361] The following set of guidelines provides a method for obtaining high purity [Nb from Nb coins having Zn or Ni (optionally isotopically enriched) coatings electroplated thereon as provided herein. 61 Cu]CuCl2, 61 This protocol allows for the production of Cu targets of all types. Specific details are also provided for deuteron and proton irradiation, respectively. Following this protocol, the [ 61 Cu]Cl2 composition was produced. [Table 10-1] [Table 10-2] [Table 10-3] [Table 10-4] [Table 10-5]

[0362] [ 61 Purification and Characterization of Cu]CuCl2 and Waste Streams The solid target irradiation material was dissolved in a total volume of 7 mL of 6 M HCl with the addition of 30% hydrogen peroxide via a dissolution chamber.

[0363] Separation and purification were achieved using a cassette-based FASTlab platform using TBP (tributyl phosphate-based) resin (1 mL) (particle size 50-100 μm; pre-packed, Triske) and then weakly basic (tertiary amine; TK201) resin (2 mL) (particle size 50-100 μm; pre-packed, Triske) pre-conditioned with HO (7 mL) and HCl (10 M, 7 mL), respectively. Cassette reagent vials were prepared using concentrated HCl (Optima grade, Fisher Scientific), NaCl (ACS, Fisher Scientific), and Milli-Q water (Millipore system, 18 MΩ cm resistivity). 6 M HCl (2 × 4.2 mL), 0.05 M HCl with 5 M NaCl (4.2 mL), and then subsequent 61 Cu was purified on two subsequent ion exchange resins in the FASTlab synthesis unit. 1) The acid-adjusted dissolution solution (approximately 7 mL) was loaded onto both columns in series and directed to the "Ni collection fraction." The TBP resin retained the Fe 3+ It acts as a guard column by quantitatively retaining ions, and Cu 2+ and Co 2+ The complex was quantitatively retained on a tertiary amine (TK201) resin. 2) To maximize Ni recovery for future recycle, both columns were washed with 6 M HCl (4 mL). 3) The TK201 column was washed with 4.5 M HCl (5.5 mL) to elute most of the cobalt salts. 4) The TK201 column was washed with 5M NaCl in 0.05M HCl (4 mL) to reduce residual acid on the resin and further remove residual cobalt salts. 5) Wash the TK201 column with 0.05 M HCl (3 mL) and 61 Cu]CuCl2 was quantitatively eluted.

[0364] The obtained plating material [ 61 The [Cu]CuCl solutions had an average radioactivity of 1.0–4.5 GBq (Figure 20). This radioactivity was measured using a Comecer dose calibrator, and its radionuclide purity was determined by a PSI (Switzerland) gamma spectrometer (Figure 22).

[0365] Gamma spectroscopy measurements were performed to identify any radionuclides, particularly long-lived radionuclides. These results demonstrate that the niobium backing material is more sensitive to the ion beam radiation than the silver backing material when utilizing the methods disclosed herein. nat Ni and 61 The results show an 89.3% and 94% reduction in Ni impurities (Figures 20 and 21). ICP-MS measurements were performed on the non-radioactive lysate product by Labor Veritas (Switzerland) to monitor the elemental impurities present in the product according to ICH-Q3D (Figure 23). All detected impurities were within the regulated ICH-Q3D concentrations (see ICH-Q3D Guidelines, pg 25).

[0366] Highly enriched 61 Ni plating is also achieved by proton irradiation (typically 80 μA to 100 μA, 13 MeV protons, 1 to 2 hours, and 61 Higher yields and industrial production using Cu (up to one half-life of Cu) were possible with the same plating parameters as above.

[0367] Using Nb backing coins nat Ni(d,n) 61Cu and 60 Ni(d,n) 61 Prepared from Cu 61 Purity and radioactivity assessment of Cu]CuCl2 compositions. Examples include Nb backings, Ni electrodeposited coins, and natural nickel targets enriched as coins and targets. 60 Coins containing Ni, i.e., each nat Ni(d,n) 61 Cu and 60 Ni(d,n) 61 Produced using a cobalt radioisotope produced by deuteron irradiation using Cu 61 Information regarding the radioactivity of Cu is presented. The irradiated material was dissolved and purified as described above.

[0368] The obtained and purified 61 Cu]Cu product and natural Ni / Nb target material and 60 The waste generated during the purification of the products of deuteron irradiation of Ni / Nb target material was treated, analyzed by gamma spectroscopy and presented below.

[0369] Natural Nickel / Nb coins and enriched 60 Thick target yield calculations based on TENDL-2019 using isotopic abundances of Ni / Nb coins.

[0370] Radioactive cobalt content Table 5 shows nat The radioactivity of the cobalt radioisotope in the different fractions after FASTlab purification is included as an average of three measurements (n = 3 irradiations) using a Ni / Nb target coin. The radioactivity was extrapolated to 3 hours, 50 μA beam, EoB (end of bombardment) + 2 hours. 61 The radioactivity of Cu]CuCl2 was experimentally determined and found to be approximately 80% of the estimate based on TENDL-2019.

[0371] Generated for deuteron irradiation at 8.4 MeV, 50 μA for 3 hours, 80% efficiency (EoB+2 hours)61 Radioactivity of Cu: 3052MBq. Time course of cobalt radioisotopes and 61 See also Figure 18 for the corresponding change in Cu purity. [Table 11]

[0372] Table 6 shows the target metals enriched to 99% 60 The calculated activity of the cobalt radioisotope obtained by using Ni is included. The activity was extrapolated to a 3-hour, 50 μA beam, EoB (end of bombardment) + 2 hours. 61 The radioactivity of Cu was calculated.

[0373] Generated by deuteron irradiation at 8.4 MeV, 50 μA for 3 hours with 80% efficiency (EoB+2 hours) 61 Radioactivity of Cu: 11,552 MBq. Time course of cobalt radioisotopes and 61 See also Figure 19 for the corresponding change in Cu purity. [Table 12]

[0374] Radioactivity and chemical purity Based on a combination of theoretical calculations and experimental results, nat Deuteron irradiation of Ni / Nb target coins produced [ 61 Cu]CuCl2 purity, enriched 60 Deuteron irradiation of Ni / Nb target coins [ 61 Cu]CuCl2.

[0375] Table 7 shows the results of the target metals for 50 μA, 3 hours of deuteron irradiation after FASTlab purification. nat Generated by Ni 61 Cu] CuCl2 solution and the extrapolated radioactive cobalt content 61 Indicates Cu purity. [Table 13]

[0376] Assuming a product expiration time of 8 hours after EoB, less than 0.03% of non-Cu radioisotopes ( 56 Co and 58 Co) would remain in the copper fraction. This value was lower than the permissible limit for Ga-68 cyclotron production as found in the Pharmacopoeia (0.1% at expiry for non-Ga radioisotopes):

[0377] nat Derived from Ni irradiation 64 Cu (approximately 5% content at expiration) is the main impurity, and it is found to be more resistant to longer exposure times or shelf life. 61 Cu reduces the radioisotopic purity of the product (shown as the grey curve in Figure 19).

[0378] Table 8: Post-FASTlab purification 61 Cu activity and purity 60 Ni / Nb Target Coin Analysis Figure 19 is generated [ 61 Cu] CuCl2 solution and the extrapolated radioactive cobalt content 61 Indicates Cu purity. [Table 14]

[0379] Assuming a product expiration time of 8 hours after EoB, less than 0.01% of non-Cu radioisotopes ( 56 Co and 58 Co) remained in the Cu fraction. This value is found in the Pharmacopoeia 68 This was 10 times lower than the limit allowed for Ga cyclotron production (0.1%* at expiration for non-Ga radioisotopes).

[0380] Copper fraction less than 0.02% at 8 hours expiration time after EoB 64 Cu remains, 68 This was 100 times lower than the specifications required for Ga ( 68 2% Ga radioisotope was allowed for Ga).

[0381] Generated from Ni / Nb target coins 61 Purity of Cu]CuCl2: Comparison with commercially available radionuclides Table 9 compares the regulatory specifications for purity of commercially available radionuclides for natNi / Nb and enriched Ni / Nb after FASTlab purification. 60 High purity [ 61 Cu]CuCl2. [Table 15]

[0382] The first notable comparison is the 68 Cyclotron production of Ga also produces long-lived radionuclides (see, for example, Applied Radiation and Isotopes 65(10), 1101-1107, IAEA-TECDOC-1863 Gallium-68 Cyclotron Production), especially 66 Zn(p,pn) 65 from Zn decay 65 Zn (half-life = 244 days) is produced. 68 Approximately 0.365% of the Zn starting target metal 66 Zn, about 770 Bq 65 Zn is produced from a 50 μA, 3-hour beam with an energy of 13 MeV in a thick target (TENDL-2019 based calculations). 66 Using natural Zn with an abundance of 27.7% in Zn, 58 kBq 65 Zn is produced in a single 3-hour beam run at 50 μA. Therefore, the isotopic purity of Zn in the target metal is very important.

[0383] [ 61 Similar to the formation of Cu]CuCl2, [ 64 Cyclotron production of Cu]CuCl2 also involves long-lived cobalt radionuclides, i.e.55 Co, 57 Co, 58 Co and 60 Co is produced (see, for example, Nuclear Medicine & Biology, Vol. 24, pp. 35-43, 1997, "Applied Radiation and Isotopes" 68 (2010) 5-13). By operating with a depleted beam of less than 13 MeV, ( 64 Ni(p,na) 60 (from Co) 60 Co was reduced to 1 Bq per 50 μA, 3-hour run. For beam energies below 13 MeV, 58 Ni(p,a) 55 Co formed from the reaction 55 Co remains the main impurity (half-life = 17.53 hours). 57 The 170 Bq of Co is mostly 60 Ni(p,a) 57 Co was formed at about 170 Bq under these conditions.

[0384] Note: These estimates are based on the TENDL-2019 cross-sectional data and enrichment data, as follows: 64 Calculated from thick target yield using Ni isotopic abundance: 0.00376% 58 Ni, 0.00298% 60 Ni, 0.0058% 61 Ni, 0.135% 62 Ni, 99.858% 64 Ni).

[0385] 5. Conclusion Generated after deuteron irradiation 61 The experimental activity of Cu is approximately 80% of the theoretical yield calculated from the TENDL-2019 cross-sectional data.

[0386] 61 The main long-lived nuclides in the radioactive waste fraction from the cyclotron production of Cu are 56 Co, 57 Co, 58 Co and 60Co is a radioactive cobalt species. 56 Co, 57 Co and 58 Co was calculated to have decayed below the regulatory clearance limit (LL*), 60 leaving only Co. *Clearance limit (LL) means the value corresponding to the specific activity level of a material at which the handling of this material is no longer subject to mandatory authorization or supervision.

[0387] 99% enrichment 60 Ni or 61 The target coin with Ni is 61 The yield and purity of the Cu product were improved. Using these targets, 61 The extrapolated purity of Cu is 64 It is higher because Cu is not formed as a radioisotopic impurity. 56 Co and 60 The Co content was reduced by 100 times. 57 The amount of Co increased (but the radioactivity was low), 58 The amount of Co increased (however, 56 Co / 58 decays below LL before Co).

[0388] Example 5: Radioactive label [ 61 Cu]Cu-NODAGA-1 and [ 61 Cu]Cu-NODAGA-3 An aliquot of the conjugate (3–6 nmol, 1 mg / mL in water) was diluted with 0.25–0.30 mL of ammonium (or sodium) acetate (0.5 M pH 8), followed by 0.1–0.7 mL of [ 61Cu]CuCl2 was added (70-240 MBq). The reaction mixture was incubated at room temperature (approximately 20-25 °C) for 15 minutes. The pH of the reaction mixture was 5-6. Quality control was performed by reverse-phase high-performance liquid chromatography (RP-HPLC) connected to a radio-detector (radio-HPLC). A Phenomenex Jupiter Proteo C12 (90 Å, 250 × 4.6 mm) column was used, with a gradient of 15-80% B in 8 minutes (A = HO [0.1% TFA], B = ACN [0.1% TFA]), at a flow rate of 1 mL / min. The radio-HPLC results are shown in Table 10 below.

[0389] [ 61 Cu]Cu-NODAGA-2 and [ 61 Cu]Cu-NODAGA-4 61 Preparation of Cu-labeled conjugates involves dissolving 1.5–3 nmol of the corresponding conjugate (as a 1 mg / mL solution) in 125–300 μL of ammonium acetate (0.5 M, pH 8) in 50–200 μL of [ 61 The reaction was performed by incubation with [Cu]CuCl2 (33–70 MBq). A pH check was performed to ensure the necessary conditions for the reaction (pH ≥ 5). The reaction mixture was incubated at room temperature for 10 min. Quality control and stability testing were performed by radio-HPLC on a Shimadzu SCL-40 connected to a GABI radioactivity-HPLC-flow monitor γ-spectrometer (Elysia raytest, Straubenhardt, Germany). Analysis of the radioligand was performed using a Phenomenex Jupiter Proteo C12 (90 Å, 250 × 4.6 mm) column with a gradient of 15–80% B over 8 min (A = HO [0.1% TFA], B = ACN [0.1% TFA]) at a flow rate of 1 mL / min. The results are shown in Table 10. [Table 16]

[0390] All conjugates were obtained in very high yields and purity. 61 Labeled with Cu. Uncomplexed61 No further purification steps were required to remove Cu from the reaction mixture, allowing direct use of the formed radiotracer.

[0391] Example 6: Partition coefficient (Log D) The lipophilicity / hydrophilicity of the radioactive tracer was assessed by determining the partition coefficient (D) between the aqueous and organic phases according to the "shake flask" method and expressed as log D (pH = 7.4). A pre-saturated mixture of 500 μL of 1-octanol and 500 μL of PBS pH 7.4 (phosphate-buffered saline) was added to a pre-lubricated Eppendorf tube. A 10 μL aliquot of 10 pmol of radioligand was added to this mixture, shaken for 30 min, and then centrifuged at 3,000 rcf for 10 min to achieve phase separation. 100 μL aliquots were removed from the 1-octanol and PBS phases, and the radioactivity was measured in a γ-counter. The partition coefficient was calculated as the average log ratio of the radioactivity in the organic and PBS fractions. The results are shown in Table 11 and Figure 1. [Table 17] Results are means ± standard deviations from at least two separate experiments, each in triplicate.

[0392] Example 7: In vitro hFAP inhibition assay The enzymatic activity of hFAP on the substrate Z-Gly-Pro-AMC was measured at room temperature in a microtiter plate reader, monitoring fluorescence at an excitation wavelength of 360 nm and an emission wavelength of 465 nm. The assay was performed by mixing substrate (20 μM), hFAP (200 pM, constant), and inhibitor in assay buffer (50 mM Tris, 1 M NaCl, 1 mg / mL BSA, pH = 7.5) with serial dilutions of the inhibitor ranging from 250 nM to 2 fM, 1:2, in a total volume of 20 μL. FAPI-46 was used as a positive control. Experiments were performed in triplicate, and mean fluorescence values ​​were fitted using Graph Pad Pri-sm 9 (using the formula: Y = bottom + (top - bottom) / (1 + ((X^HillSlope) / (IC50^HillSlope))). IC 50 The value is defined as the concentration of inhibitor required to reduce enzyme activity by 50% after addition of substrate. The results are shown in Table 12 and Figure 2. [Table 18]

[0393] Example 8: In vitro cellular uptake 61 Cu-NODAGA-1 and 61 Cu-NODAGA-3 Cellular uptake was tested in vitro using intact cells seeded overnight in 6-well plates. On the day of the experiment, cells were washed and incubated with 100 μg of IgG alone or in the presence of blocking agents at different time points to distinguish between specific and nonspecific uptake. 61The cells were incubated with each of the Cu-labeled conjugates. At each time point investigated, the medium containing unbound (free) radiotracer was removed, followed by two washes with ice-cold phosphate-buffered saline. The cells were then treated with ice-cold glycine solution (0.05 M, pH 2.8) for 2 × 5 min to detach the cell surface-bound radiotracer (acid release). Cells containing internalized radiotracer were then detached with 1 M NaOH at 37 °C and collected for measurement. The amount of specific cell surface-bound and internalized radiotracer is expressed as a percentage of the total radioactivity irradiated after subtracting nonspecific values. In HT-1080.hFAP (FAP-positive) and HT-1080.wt (FAP-negative) cells, [ 61 Cu]Cu-NODAGA-1,[ 61 Cu]Cu-NODAGA-3 and [ 61 Cu]Cu-NODAGA-FAPI-46 (0.2 nM) was evaluated. The internalized and cell surface-associated fractions of the tested radiotracers are reported in Table 13. Values ​​are expressed as % of the delivered radioactivity and refer to specific uptake calculated after subtracting the nonspecific value (measured in the presence of the FAP-nonexpressing cell line HT-1080.wt) from the total value (specific = total - nonspecific). [Table 19]

[0394] [ 61 Cu]Cu-NODAGA-2 and [ 61 Cu]Cu-NODAGA-4 Once thawed, HT-1080.hFAP (FAP-positive), HT-1080.wt (FAP-negative), HEK-293.hFAP, and HEK-293.wt cells were cultured in MEM medium supplemented with fetal bovine serum (10% FBS) and penicillin-streptomycin (1%) at 37°C and 5% CO. For passage, cells were detached using trypsin-EDTA 0.05% upon reaching 90% confluence and replated at a dilution of 1:4 / 1:12 (HT-1080) or 1:10 / 1:20 (HEK-293).

[0395] HT-1080.hFAP and HT-1080.wt cells were cultured at 1.8 × 10 in 400 μL of medium 24 h before the experiment. 5 Cells were seeded into a 24-well plate at a concentration of 100 cells / well. Cells were then preconditioned in 360 μL of assay medium (MEM medium without supplements) at 37°C for 60 minutes. 61 A 2 nM solution of Cu-labeled radioligand was added, and the cells were incubated at 37 °C. Cell uptake was interrupted at different time points (15 min, 1 h, and 4 h) by washing twice with ice-cold PBS. The cell surface-bound radioligand was obtained by washing the cells twice with ice-cold glycine buffer (pH 2.8) followed by collection of the internalized fraction with 1 M NaOH. The radioactivity of each fraction was measured using a γ-counter (Cobra II). The results are expressed as a percentage of the irradiated radioactivity after subtracting nonspecific uptake in HT-1080.wt cells (Figures 3 and 4).

[0396] 61 The Cu-labeled FAP radiotracer was rapidly and almost completely internalized in cells expressing human FAP at 37°C, with only negligible amounts remaining on the cell surface (plasma membrane).

[0397] Example 9: Saturation binding experiments Cell membrane preparation: HEK-293.hFAP cells were grown to confluence, mechanically disaggregated, washed with PBS (pH 7.4), and resuspended in 20 mM homogenization Tris buffer (pH 7.5) containing 1.3 mM EDTA, 0.25 M sucrose, 0.7 mM bacitracin, 5 μM soybean trypsin inhibitor, and 0.7 mM PMSF. The cells were homogenized using an Ultra-Turrax, and the homogenized suspension was centrifuged at 500 × g for 10 minutes at 4 °C. The supernatant was collected in a centrifuge tube (Beckman Coulter Inc., Brea, CA, USA). This procedure was then repeated five times. The collected supernatant was centrifuged at 49,000 × g for 55 minutes at 4 °C in an ultracentrifuge (Beckman). The pellet was then resuspended in 10 mM ice-cold HEPES buffer (pH 7.5), aliquoted, and stored at −80° C. The protein concentration of these membrane suspensions was determined by the Bradford method using BSA as a standard.

[0398] Saturation experiments: 61 The association profile of Cu-labeled radioligand was investigated at different concentrations ranging from 0.075 nM to 50 nM on HEK-293 hFAP cell membranes at 37 °C. Each assay tube contained 170 μL of binding buffer (20 mM HEPES, pH 7.4, containing 4 mM MgCl2, 0.2% BSA, 20 mg / L bacitracin, 20 mg / L PMSF, and 200,000 KIU / L aprotinin). Incubation was initiated by adding 30 μL of 10x the final concentration of radioligand solution and 100 μL of cell membrane suspension, resulting in 10 μg of protein per well. For determination of nonspecific binding, 140 μL of the above binding buffer was added along with 30 μL of FAPI-46 (0.1 mM). The bound fraction was plotted against the corresponding radioligand concentration at equilibrium. Dissociation constant (KD) and maximum binding capacity (Bmax) values ​​were calculated using GraphPad Software Inc., Prism 7 (San Diego, CA, USA) (Table 14 and Figure 5). [Table 20]

[0399] Example 10: Mouse studies All animal experiments were performed in accordance with Swiss animal welfare laws and regulations under license number 30515 granted by the Veterinary Office (Department of Health) of Canton Basel-Stadt.

[0400] Tumor transplantation: 4-6 week-old female athymic nude-Foxn1nu / Foxn1+ mice (Envigo, The Netherlands) were implanted with 5-10 × 10 tumor cells suspended in 100 μL of PBS. 6 HT-1080.hFAP cells were injected subcutaneously into the right shoulder or right flank, with 5–10 × 10 cells suspended in 100 µL of PBS. 6 HT-1080 wild-type cells were injected into the contralateral shoulder or flank. Tumors grew to 100–200 mm 3 The cells were grown to an average volume of 1000 kJ / ml.

[0401] Biodistribution study: Xenograft mice were randomized (n=5 per group) 61 Cu-labeled radioligand (100 μL, 500 pmol, 0.8–1 MBq) was injected intravenously via the tail vein. Mice were euthanized by CO2 asphyxiation at 1 and 4 hours post-injection. Organs of interest and blood were harvested, rinsed of excess blood, blotted dry, weighed, and counted in a γ-counter. Samples were counted against appropriately diluted aliquots of the injection solution as a standard, and results are expressed as the percentage of injected radioactivity per gram of tissue (% IA / g) ± SD. Results are shown in Tables 15A–B and Figures 6–11. [Table 21] [Table 22]

[0402] [ 61 Cu]Cu-NODAGA-1,[ 61Cu]Cu-NODAGA-2,[ 61 Cu]Cu-NODAGA-3,[ 61 Cu]Cu-NODAGA-4 and [ 61 Cu]Cu-NODAGA-1 showed high accumulation in FAP-positive (HT-1080.hFAP) tumors and mouse FAP-positive tissues, such as bone marrow.

[0403] PET / CT Imaging: Mice bearing FAP-positive and FAP-negative xenografts were subjected to the PET / CT imaging of the present disclosure. 61 Cu-labeled radioligand or [ 61 [Cu]Cu-NODAGA-FAPI-46 (100 μL / 500 pmol / 6-12 MBq) was injected intravenously. Mice were anesthetized with 1.5% isoflurane, and dynamic PET scans were acquired for 1 h at the time of injection of the radiotracer. Mice were euthanized with CO2 at 4 h pi, and static PET scans were acquired for 30 min.

[0404] PET / CT images were acquired using a β-CUBE PET scanner system (Molecubes, Gent, Belgium) with a spatial resolution of 0.85 mm and an axial field of view of 13 cm. Dynamic PET scans were acquired for 60 minutes. All PET scans were attenuation-corrected by the ordered subset expectation maximization (OSEM) algorithm and reconstructed into a 192 × 400 × 384 matrix using 30 iterations, a voxel size of 400 × 192 × 400 μm, and 15 minutes per frame. Attenuation correction was applied to the PET data using the CT data. CT scans were performed in the head-on supine position using a NanoSPECT / CT™ scanner (Bioscan Inc.). First, a topogram and helical CT scan of the whole mouse were acquired using the following parameters: X-ray tube current: 177 μA, X-ray tube voltage: 45 kVp, 90 seconds, and 180 frames per rotation, with a pitch of 1. CT images were reconstructed using CTReco (version r1.146) with a standard filtered backprojection algorithm (accurate cone beam) and post-filtering (RamLak, 100% frequency cutoff) to obtain a pixel size of 0.2 mm. Co-registered PET / CT images were visualized using maximum intensity projection (MIP) with VivoQuant software (version 4.0). (Figures 12–15, and Figure 24).

[0405] Prior to the 4-hour scan, residual PET radioactivity in the mouse body 4 hours pi was measured (Table 16). 61 Cu]Cu-NODAGA-FAPI-46 and [ 61 Cu]Cu-NODAGA-1 showed the highest retention rate in the body, and [ 61 Cu]Cu-NODAGA-4 showed the lowest value. Due to the physical properties of the radionuclides, [ 68 Ga]Ga-FAPI-46 was not evaluated 4 hours pi. [Table 23]

[0406] 7. Equivalents and Incorporation by Reference While the present disclosure provided has been particularly shown and described with reference to preferred and various alternative embodiments, those skilled in the art will understand that various changes in form and details can be made herein without departing from the spirit and scope of the present disclosure provided.

[0407] All references, issued patents, and patent applications cited within the text of this specification are incorporated herein by reference in their entirety for all purposes. In particular, U.S. Provisional Patent Applications Nos. 63 / 409,684 (filed September 23, 2022); 63 / 409,687 (filed September 23, 2022); 63 / 416,479 (filed October 14, 2022); 63 / 520,329 (filed August 17, 2023); and 63 / 520,323 (filed August 17, 2023) are incorporated herein by reference in their entirety. Additionally, the following U.S. non-provisional patent applications filed concurrently with this application are also incorporated herein by reference in their entirety: · An application entitled "SOLID TARGET SYSTEMS FOR THE PRODUCTION OF HIGH PURITY RADIONUCLIDE COMPOSITIONS," filed September 25, 2023, under Attorney Docket No. 39973-53109 (001US); and An application entitled "HIGH PURITY COPPER RADIOPHARMACEUTICAL COMPOSITIONS AND DIAGNOSTIC AND THERAPEUTIC USES THEREOF," filed September 25, 2023, under Attorney Docket No. 39973-52915 (002US).

Claims

1. 1. A compound, wherein the compound is a compound of formula I: 【Chemical 1】 R １ is R ａ and R ２ and R ３ are R ａ or together with the nitrogen atom to which they are attached and C ２－９ forming a heterocyclic ring; R ４ is H, an amine protecting group, or -LT; R ａ independently for each occurrence, H, C １－１０ Alkyl, C ２－１０ Alkenyl, C ３－１０ Alkynyl, C ３－１０ Cycloalkyl, C ６－１０ Aryl, C ２－９ heterocyclyl, or C ５－９ heteroaryl, optionally selected from -OH, -OR', =O, =S, -SH, -SR', -NH ２ , -NHR', -N(R') ２ , —NHCOR′, —NR′COR′, halogen, —CN, —CO ２ H, -CO ２ R', -CHO, -COR', -CONH ２ , -CONHR', -CON(R') ２ , -NO ２ , -OP(O)(OH) ２ , -SO ３ H, -SO ３ R', -SOR', and -SO ２ R' is substituted with one or more substituents selected from, １－１０ Alkyl or C ３－１０ is cycloalkyl; L is a bond or a bivalent linker; T comprises (a) a chelating moiety suitable for chelating a radionuclide, (b) an imaging agent, or (c) a drug; n is an integer from 1 to 20; m is an integer from 1 to 20; or a pharmaceutically acceptable salt thereof.

2. R １ is C １－１０ The compound of claim 1 , wherein the aryl group is alkyl.

3. R １ The compound of claim 2, wherein is methyl.

4. R １ The compound of claim 1 , wherein is H.

5. R ２ The compound of any one of claims 1 to 4, wherein is H.

6. R ３ The compound of any one of claims 1 to 5, wherein is H.

7. R ２ and R ３ together form the nitrogen atom to which they are bonded and C ２－９ The compound according to any one of claims 1 to 4, which forms a heterocycle.

8. Said C ２－９ 8. The compound of claim 7, wherein the heterocycle is a 5-, 6-, or 7-membered heterocycle.

9. Said C ２－９ 9. The compound of claim 8, wherein the heterocycle is a 6-membered heterocycle, preferably selected from piperazine, hexahydropyrimidine, hexahydropyridazine, 1,2,3-triazinane, 1,2,4-triazinane, and 1,3,5-triazinane.

10. 10. The compound of claim 9, wherein the six-membered heterocycle is piperazine.

11. Said C ２－９ 9. The compound according to claim 8, wherein the heterocycle is a five-membered heterocycle, preferably selected from pyrrolidine, pyrazolidine and imidazoline.

12. R ４ The compound of any one of claims 1 to 11, wherein is H.

13. R ４ The compound of any one of claims 1 to 11, wherein is an amine protecting group.

14. 14. The compound of claim 13, wherein the amine protecting group is selected from carbobenzyloxy (Cbz), p-methoxybenzylcarbonyl (Moz or MeOZ), tert-butyloxycarbonyl (Boc), 9-fluorenylmethyloxycarbonyl (FMOC), acetyl (Ac), benzoyl (Bz), benzyl (Bn), carbamate, p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), succinimide (i.e., cyclic imide) and tosyl (Ts), preferably tert-butyloxycarbonyl (Boc).

15. R ４ The compound of any one of claims 1 to 11, wherein is -LT.

16. 16. The compound of claim 15, wherein L is a bond.

17. 16. The compound of claim 15, wherein L is a bivalent linker.

18. 18. The compound of claim 17, wherein L is selected from an acid labile linker, a hydrolytically labile linker, an enzymatically cleavable linker, a reduction labile linker, a self-immolative linker, and a non-cleavable linker.

19. 19. The compound of claim 17 or 18, wherein L comprises one or more peptides, amino acids, glucuronides, succinimide thioethers, polyethylene glycol (PEG) units, hydrazones, mal-caproyl units, dipeptide units, valine-citrulline units, para-aminobenzyl (PAB) units, or combinations thereof.

20. 20. The compound of any one of claims 15 to 19, wherein T comprises a chelating moiety suitable for chelating a radionuclide.

21. 21. The compound of claim 20, wherein the chelating moiety does not include a radionuclide.

22. 21. The compound of claim 20, wherein the chelating moiety is chelated to a radionuclide.

23. 23. The compound of claim 22, wherein the radionuclide is selected from alpha-emitting isotopes, beta-emitting isotopes, gamma-emitting isotopes, Auger electron-emitting isotopes, X-ray-emitting isotopes, and fluorescent-emitting isotopes.

24. I'm not going to sleep. ２２５ 1.、 ５１ 、 ６６ |、 ６７ |、 ６８ [||、| １８ !|!F、 １１１ .、 １１３ｍ .、 ５２ｍ *、 ９９ｍ (c、) １８６ 2)、 １８８ 2)、 １３９ fi、 １４０ fi、 １７５ b、 １７９ b、 １５３ 3m、 １７７ｍ 、 １６６ 、 ８６ 、 ８８ 、 ９０ 、 １４９ m、 １６５ y、 １６９ ॥、 １７７ u、 ５２ e、 ４３ 3、 ４４ 3、 ４６ 3、 ４７ 3、 １４２ 0.、 １５７ 、、 １５９ 、、 ２１２ 、、 ２１３ 、、 ７２ 1.、 ７７ 1.、 ９７ __、 １０９ P、 １０５ (2) １０１ｍ (2) １１９ __、 １９７ 、 １５１ ॥、 １５３ ॥、 １６９ ॥、 ２０１ .、 １４９ (b、) １５２ (b、) １５５ (b、) １６１ (b、) ２０３ pi.、 ２１２ pi.、 １５１ m、 １５３ m、 １４２ 0.、 １４３ 0.、 ５５ o、 ６０ u、 ６１ u、 ６２ Cu, ６４ Cu, ６７ Cu, ６２ Zn, １８８ Re, １９８ Au, １９９ Au, ２２７ Th, １１１ Ag, １９９ Ag, ２１１ At, ２２３ Ra, ８８ Zr and ８９ Zr, preferably ６１ Cu, ６２ Cu, ６４ Cu and ６７ 24. The compound of claim 23, wherein the compound is selected from Cu.

25. The radionuclide ６１ 24. The compound of claim 23, wherein the compound is Cu.

26. The radionuclide ６７ 24. The compound of claim 23, wherein the compound is Cu.

27. The compound of any one of claims 20 to 26, wherein the chelating moiety comprises 2 to 8 binding moieties.

28. The chelating moiety may be DOTAGA (1,4,7,10-tetraazacyclododecane, 1-(glutaric acid)-4,7,10-triacetic acid), DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid), DOTASA (1,4,7,10-tetraazacyclododecane-1-(2-succinic acid)-4,7,10-triacetic acid), CB-DO2A (10-bis(carboxymethyl)-1,4,7,10-tetraazabicyclo[5.5.2]tetradecane), DEPA (7-[2-(bis-carboxymethylamino)-ethyl]-4,10 -bis-carboxymethyl-1,4,7,10-tetraaza-cyclododec-1-yl-acetic acid), 3p-C-DEPA (2-[(carboxymethyl)][5-(4-nitrophenyl-1-[4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl]pentan-2-yl)amino]acetic acid), TCMC (2-(4-isothiocyanobenzyl)-1,4,7,10-tetraaza-1,4,7,10-tetra-(2-carbamonylmethyl)-cyclododecane), oxo-DO3A (1-oxa-4,7,10- triazacyclododecane-5-S-(4-isothiocyanatobenzyl)-4,7,10-triacetic acid), p-NH2-Bn-oxo-DO3A (1-oxa-4,7,10-tetraazacyclododecane-5-S-(4-aminobenzyl)-4,7,10-triacetic acid), TE2A ((1,8-N,N'-bis-(carboxymethyl)-1,4,8,11-tetraazacyclotetradecane), MM-TE2A, DM-TE2A, CB-TE2A (4,11-bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane), CB- TE1A1P (4,8,11-tetraazacyclotetradecane-1-(methanephosphonic acid)-8-(methanecarboxylic acid), CB-TE2P (1,4,8,11-tetraazacyclotetradecane-1,8-bis(methanephosphonic acid), TETA (1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid), NOTA (1,4,7-triazacyclononane-N,N',N"-triacetic acid), NODA (1,4,7-triazacyclononane-1,4-diacetate), NODAGA (1,4,7-triazacyclononane-1-glutaric acid-4,7-acetic acid) (also known as NOTAGA), NODA desferoxamine (1,4,7-triazacyclononane-1,4-diyl)diacetic acid DFO), NETA ([4-[2-(bis-carboxymethylamino)-ethyl]-7-carboxymethyl-[1,4,7]triazonan-1-yl}acetic acid), TACN-™ (N,N',N",tris(2-mercaptoethyl)-1,4,7-triazacyclononane), Diamsar (1,8-diamino-3,6,10,13,16,19-hexaazabicyclo[6,6,6]eicosane, ...

28. The compound according to claim 27, wherein the compound is selected from the group consisting of 4,4'-((3,6,10,13,16,19-hexazabicyclo[6.6.6]icosan-1,8-diylbis(aza-nediyl))bis(methylene))dibenzoic acid (BaBaSar), 4,4'-((8-amino- ...

29. 29. The compound of claim 28, wherein the chelating moiety is selected from DOTAGA, DOTA, NOTA, NODAGA and NODA, preferably NODAGA.

30. 20. The compound of any one of claims 15 to 19, wherein T comprises an imaging agent.

31. 31. The compound of claim 30, wherein the imaging agent comprises a radionuclide.

32. The radionuclide １８ F. １４ C. １１ C. １３ N. ３２ P. ３５ S. １２５ I, １３１ I, １２４ I, １２３ I and １５ 32. The compound of claim 31 , wherein the compound is selected from:

33. 31. The compound of claim 30, wherein the imaging agent comprises a non-chelated radioactive moiety.

34. The non-chelated radioactive moiety is １１ C]Cu-methionine (Met), [ １８ F]F-2-fluoro-2-deoxyglucose (FDG), [ １８ F] F label C ６ - １０ aryl, and １８ F] F label C ５－９ 34. The compound of claim 33, wherein the compound is selected from heteroaryl.

35. 32. The compound of claim 31 , wherein the imaging agent comprises a chelating moiety chelated to a radionuclide.

36. 36. The compound of claim 35, wherein the radionuclide is an alpha, beta, positron, or gamma radiation emitting isotope.

37. I'm not going to sleep. ２２５ 1.、 ５１ 、 ６６ |、 ６７ |、 ６８ [||、| １８ !|!F、 １１１ .、 １１３ｍ .、 ５２ｍ *、 ９９ｍ (c、) １８６ 2)、 １８８ 2)、 １３９ fi、 １４０ fi、 １７５ b、 １７９ b、 １５３ 3m、 １７７ｍ 、 １６６ 、 ８６ 、 ８８ 、 ９０ 、 １４９ m、 １６５ y、 １６９ 、 １７７ u、 ５２ e、 ４３ 3、 ４４ 3、 ４６ 3、 ４７ 3、 １４２ 0.、 １５７ 、、 １５９ 、、 ２１２ 、、 ２１３ 、、 ７２ 1.、 ７７ 1.、 ９７ __、 １０９ P、 １０５ (2) １０１ｍ (2) １１９ __、 １９７ 、 １５１ ॥、 １５３ ॥、 １６９ ॥、 ２０１ .、 １４９ (b、) １５２ (b、) １５５ (b、) １６１ (b、) ２０３ pi.、 ２１２ pi.、 １５１ m、 １５３ m、 １４２ 0.、 １４３ 0.、 ５５ o、 ６０ u、 ６１ u、 ６２ Cu, ６４ Cu, ６７ Cu, ６２ Zn, １８８ Re, １９８ Au, １９９ Au, ２２７ Th, １１１ Ag, １９９ Ag, ２１１ At, ２２３ Ra, ８８ Zr and ８９ Zr, preferably ６１ Cu, ６２ Cu, ６４ Cu and ６７ 36. The compound of claim 35, wherein the compound is selected from Cu.

38. The radionuclide ６１ 38. The compound of claim 37, wherein the compound is Cu.

39. The compound of any one of claims 35 to 38, wherein the chelating moiety comprises 2 to 8 binding moieties.

40. The chelating moiety may be DOTAGA (1,4,7,10-tetraazacyclododecane, 1-(glutaric acid)-4,7,10-triacetic acid), DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid), DOTASA (1,4,7,10-tetraazacyclododecane-1-(2-succinic acid)-4,7,10-triacetic acid), CB-DO2A (10-bis(carboxymethyl)-1,4,7,10-tetraazabicyclo[5.5.2]tetradecane), DEPA (7-[2-(bis-carboxymethylamino)-ethyl]-4,10 -bis-carboxymethyl-1,4,7,10-tetraaza-cyclododec-1-yl-acetic acid), 3p-C-DEPA (2-[(carboxymethyl)][5-(4-nitrophenyl-1-[4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl]pentan-2-yl)amino]acetic acid), TCMC (2-(4-isothiocyanobenzyl)-1,4,7,10-tetraaza-1,4,7,10-tetra-(2-carbamonylmethyl)-cyclododecane), oxo-DO3A (1-oxa-4,7,10- triazacyclododecane-5-S-(4-isothiocyanatobenzyl)-4,7,10-triacetic acid), p-NH2-Bn-oxo-DO3A (1-oxa-4,7,10-tetraazacyclododecane-5-S-(4-aminobenzyl)-4,7,10-triacetic acid), TE2A ((1,8-N,N'-bis-(carboxymethyl)-1,4,8,11-tetraazacyclotetradecane), MM-TE2A, DM-TE2A, CB-TE2A (4,11-bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane), CB- TE1A1P (4,8,11-tetraazacyclotetradecane-1-(methanephosphonic acid)-8-(methanecarboxylic acid), CB-TE2P (1,4,8,11-tetraazacyclotetradecane-1,8-bis(methanephosphonic acid), TETA (1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid), NOTA (1,4,7-triazacyclononane-N,N',N"-triacetic acid), NODA (1,4,7-triazacyclononane-1,4-diacetate), NODAGA (1,4,7-triazacyclononane-1-glutaric acid-4,7-acetic acid) (also known as NOTAGA), NODA desferoxamine (1,4,7-triazacyclononane-1,4-diyl)diacetic acid DFO (desferoxamine), NETA ([4-[2-(bis-carboxymethylamino)-ethyl]-7-carboxymethyl-[1,4,7]triazonan-1-yl}acetic acid), TACN-™ (N,N',N",tris(2-mercaptoethyl)-1,4,7-triazacyclononane), Diamsar (1,8-diamino-3,6,10,13,16,19-hexazabicyclo(6,6,6)eicosane, 3,6,10,13,16,19-hexazabicyclo 40. The compound of claim 39, wherein the compound is selected from the group consisting of 4-((8-amino-3,6,10,13,16,19-hexazabicyclo[6.6.6]icosan-1,8-diamine), 4-((8-amino-3,6,10,13,16,19-hexazabicyclo[6.6.6]icosan-1,8-diylbis(aza-nediyl))bis(methylene))dibenzoic acid (BaBaSar).

41. 41. The compound of claim 40, wherein the chelating moiety is selected from DOTAGA, DOTA, NOTA, NODAGA and NODA, preferably NODAGA.

42. 31. The compound of claim 30, wherein the imaging agent is a fluorescent dye.

43. 43. The compound of claim 42, wherein the fluorescent dye is selected from one of the classes of xanthene, acridine, oxazine, cyanine, styryl dye, coumarin, porphine, metal-ligand-complex, fluorescent protein, nanocrystal, perylene, boron-dipyrromethene, and phthalocyanine.

44. The compound of any one of claims 15 to 19, wherein T comprises a drug.

45. 45. The compound of claim 44, wherein the drug comprises a chelating moiety chelated to a radionuclide.

46. 46. ​​The compound of claim 45, wherein the radionuclide is selected from alpha-emitting and beta-emitting isotopes.

47. I'm not going to sleep. ２２５ 1.、 ５１ 、 ６６ |、 ６７ |、 ６８ [||、| １８ !|!F、 １１１ .、 １１３ｍ .、 ５２ｍ *、 ９９ｍ (c、) １８６ 2)、 １８８ 2)、 １３９ fi、 １４０ fi、 １７５ b、 １７９ b、 １５３ 3m、 １７７ｍ 、 １６６ 、 ８６ 、 ８８ 、 ９０ 、 １４９ m、 １６５ y、 １６９ 、 １７７ u、 ５２ e、 ４３ 3、 ４４ 3、 ４６ 3、 ４７ 3、 １４２ 0.、 １５７ 、、 １５９ 、、 ２１２ 、、 ２１３ 、、 ７２ 1.、 ７７ 1.、 ９７ __、 １０９ P、 １０５ (2) １０１ｍ (2) １１９ __、 １９７ 、 １５１ ॥、 １５３ ॥、 １６９ ॥、 ２０１ .、 １４９ (b、) １５２ (b、) １５５ (b、) １６１ (b、) ２０３ pi.、 ２１２ pi.、 １５１ m、 １５３ m、 １４２ 0.、 １４３ 0.、 ５５ o、 ６０ u、 ６１ u、 ６２ Cu, ６４ Cu, ６７ Cu, ６２ Zn, １８８ Re, １９８ Au, １９９ Au, ２２７ Th, １１１ Ag, １９９ Ag, ２１１ At, ２２３ Ra, ８８ Zr and ８９ Zr, preferably ６１ Cu, ６２ Cu, ６４ Cu and ６７ 47. The compound of claim 45 or 46, wherein the compound is selected from Cu.

48. The radionuclide ６７ 48. The compound of claim 47, wherein the compound is Cu.

49. 49. The compound of any one of claims 45 to 48, wherein the chelating moiety comprises 2 to 8 binding moieties.

50. The chelating moiety may be DOTAGA (1,4,7,10-tetraazacyclododecane, 1-(glutaric acid)-4,7,10-triacetic acid), DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid), DOTASA (1,4,7,10-tetraazacyclododecane-1-(2-succinic acid)-4,7,10-triacetic acid), CB-DO2A (10-bis(carboxymethyl)-1,4,7,10-tetraazabicyclo[5.5.2]tetradecane), DEPA (7-[2-(bis-carboxymethylamino)-ethyl]-4,10 -bis-carboxymethyl-1,4,7,10-tetraaza-cyclododec-1-yl-acetic acid), 3p-C-DEPA (2-[(carboxymethyl)][5-(4-nitrophenyl-1-[4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl]pentan-2-yl)amino]acetic acid), TCMC (2-(4-isothiocyanobenzyl)-1,4,7,10-tetraaza-1,4,7,10-tetra-(2-carbamonylmethyl)-cyclododecane), oxo-DO3A (1-oxa-4,7,10- triazacyclododecane-5-S-(4-isothiocyanatobenzyl)-4,7,10-triacetic acid), p-NH2-Bn-oxo-DO3A (1-oxa-4,7,10-tetraazacyclododecane-5-S-(4-aminobenzyl)-4,7,10-triacetic acid), TE2A ((1,8-N,N'-bis-(carboxymethyl)-1,4,8,11-tetraazacyclotetradecane), MM-TE2A, DM-TE2A, CB-TE2A (4,11-bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane), CB- TE1A1P (4,8,11-tetraazacyclotetradecane-1-(methanephosphonic acid)-8-(methanecarboxylic acid), CB-TE2P (1,4,8,11-tetraazacyclotetradecane-1,8-bis(methanephosphonic acid), TETA (1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid), NOTA (1,4,7-triazacyclononane-N,N',N"-triacetic acid), NODA (1,4,7-triazacyclononane-1,4-diacetate), NODAGA (1,4,7-triazacyclononane-1-glutaric acid-4,7-acetic acid) (also known as NOTAGA), NODA desferoxamine (1,4,7-triazonane-1,4-diyl)diacetic acid DFO), NETA ([4-[2-(bis-carboxymethylamino)-ethyl]-7-carboxymethyl-[1,4,7]triazonan-1-yl}acetic acid), TACN-™ (N,N',N",tris(2-mercaptoethyl)-1,4,7-triazacyclononane), Diamsar (1,8-diamino-3,6,10,13,16,19-hexazabicyclo[6,6,6]eicosane, ...

50. The compound of claim 49, wherein the compound is selected from the group consisting of 4,4'-((3,6,10,13,16,19-hexazabicyclo[6.6.6]icosan-1,8-diylbis(aza-nediyl))bis(methylene))dibenzoic acid (BaBaSar), 4,4'-((8-amino- ...

51. 51. The compound of claim 50, wherein the chelating moiety is selected from DOTAGA, DOTA, NOTA, NODAGA and NODA, preferably NODAGA.

52. The drug may be a peptide, an oligopeptide, a retro-inverso oligopeptide, a protein, a protein analogue in which at least one non-peptide bond replaces a peptide bond, an apoprotein, a glycoprotein, an enzyme, a coenzyme, an enzyme inhibitor, an amino acid and its derivatives, a receptor and other membrane proteins; an antigen and an antibody thereto; a hapten and an antibody thereto; a hormone, a lipid, a phospholipid, a liposome; a toxin; an antibiotic; an analgesic; a bronchodilator; a beta-blocker; an antibacterial agent; an antihypertensive agent; an antiarrhythmic agent, a cardiac glycoside, an antianginal agent 45. The compound of claim 44, selected from cardiovascular agents, including drugs and vasodilators; central nervous system-acting drugs, including stimulants, psychotropics, antimanics, and depressants; antivirals; antihistamines; cancer drugs, including chemotherapeutic agents; tranquilizers; antidepressants; H-2 antagonists; anticonvulsants; antiemetics; prostaglandins and prostaglandin analogs; muscle relaxants; anti-inflammatory substances; stimulants; decongestants; antiemetics; diuretics; antispasmodics; antiasthmatics; antiparkinsonian agents; expectorants; cough suppressants; mucolytics; and minerals and nutritional additives.

53. 45. The compound of claim 44, wherein the drug is a cytotoxic agent.

54. The drug may be adrenocorticoids and corticosteroids, alkylating agents, antiandrogens, antiestrogens, androgens, aclamycin and aclamycin derivatives, estrogens, antimetabolites such as cytosine arabinoside, purine analogs, pyrimidine analogs, methotrexate, busulfan, carboplatin, chlorambucil, cisplatin and other platinum compounds, taxanes such as tamoxifen, taxol, paclitaxel, paclitaxel derivatives, Taxotere t®, maytansine and its analogs and derivatives, cyclophosphamide, daunomycin, doxorubicin, rhizoxin, T2 toxin, plant alkaloids, prednisone, hydroxyurea, teniposide, mitomycin, discodermolide, microtubule inhibitors, epothilones, tubulysins, cyclopropylbenz[e]indolone, seco-cyclopropylbenz[e]indolone, O-Ac-seco-cyclopropylbenz[e]indolone, bleomycin and any other antibiotics substances, nitrogen mustards, nitrosulphur, vincristine, vinblastine and analogs and derivatives thereof, such as deacetylvinblastine monohydrazide, colchicine, colchicine derivatives, allocolchicine, thiocolchicine, trityl cysteine, halichondrin B, dolastatins such as dolastatin 10, amanitin, such as α-amanitin, camptothecin, irinotecan and other camptothecin derivatives thereof, geldanamycin and geldanamycin derivatives, escherichia coli, erythroderma, erythrostacil, erythrostacil-like compounds ...

54. The compound of claim 53, which is a cytotoxic agent selected from tramustine, nocodazole, MAP4, colcemid, inflammatory and pro-inflammatory agents, peptide and peptidomimetic signal transduction inhibitors, penicillins, cephalosporins, vancomycin, erythromycin, clindamycin, rifampin, chloramphenicol, aminoglycoside antibiotics, gentamicin, amphotericin B, acyclovir, trifluridine, ganciclovir, zidovudine, amantadine, and ribavirin.

55. 55. The compound of any one of claims 1 to 54, wherein n is an integer from 1 to 10.

56. 56. The compound of claim 55, wherein n is an integer from 1 to 5.

57. 57. The compound of claim 56, wherein n is 2.

58. 58. The compound of any one of claims 1 to 57, wherein m is an integer from 1 to 10.

59. 59. The compound of claim 58, wherein m is an integer from 1 to 5.

60. 60. The compound of claim 59, wherein m is 2.

61. The compound of claim 1, wherein the compound is a compound of formula Ia: 【Chemistry 2】

62. The compound of claim 1, wherein the compound is a compound of formula Ib: 【Chemistry 3】

63. R １ 63. The compound of claim 61 or 62, wherein is H.

64. R １ is C １－１０ 63. The compound of claim 61 or 62, which is alkyl.

65. R １ 65. The compound of claim 64, wherein is methyl.

66. R ４ The compound of any one of claims 61 to 65, wherein is H.

67. R ４ 66. The compound of any one of claims 61 to 65, wherein is an amine protecting group.

68. 68. The compound of claim 67, wherein the amine protecting group is selected from carbobenzyloxy (Cbz), p-methoxybenzylcarbonyl (Moz or MeOZ), tert-butyloxycarbonyl (Boc), 9-fluorenylmethyloxycarbonyl (FMOC), acetyl (Ac), benzoyl (Bz), benzyl (Bn), carbamate, p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), succinimide (i.e., cyclic imide) and tosyl (Ts), preferably tert-butyloxycarbonyl (Boc).

69. R ４ The compound of any one of claims 61 to 65, wherein is -LT.

70. R １ is H or methyl; n is an integer from 1 to 5; T comprises a chelating moiety chelated to a radionuclide, said chelating moiety being selected from DOTAGA, DOTA, NOTA, NODAGA, and NODA; The radionuclide ６１ Cu, ６４ Cu and ６７ Cu; 70. The compound of claim 69.

71. the compound is selected from: 【Table 1】 or a pharmaceutically acceptable salt thereof.

72. the compound is selected from: 【Table 2】 or a pharmaceutically acceptable salt thereof.

73. the compound is selected from: 【Table 3-1】 【Table 3-2】 or a pharmaceutically acceptable salt thereof, and *Cu is ６１ Cu, ６２ Cu, ６４ Cu and ６７ Cu, especially ６１ Cu and ６７ 2. The compound of claim 1, wherein the compound is selected from Cu.

74. 1. A compound, wherein the compound is a compound of formula II: 【Chemistry 4】 R ３ H, C １－１０ Alkyl, C ２－１０ Alkenyl, C ３－１０ Alkynyl, C ３－１０ Cycloalkyl, C ６－１０ Aryl, C ２－９ heterocyclyl, or C ５－９ heteroaryl, optionally selected from -OH, -OR', =O, =S, -SH, -SR', -NH ２ , -NHR', -N(R') ２ , —NHCOR′, —NR′COR′, halogen, —CN, —CO ２ H, -CO ２ R', -CHO, -COR', -CONH ２ , -CONHR', -CON(R') ２ , -NO ２ , -OP(O)(OH) ２ , -SO ３ H, -SO ３ R', -SOR', and -SO ２ R' is substituted with one or more substituents selected from, １－１０ Alkyl or C ３－１０ is cycloalkyl; or R ３ together with the L moiety, the nitrogen atom to which they are attached and C ２－９ forming a heterocyclic ring; L is a bivalent linker, preferably up to 20 atoms in length; or a pharmaceutically acceptable salt thereof.

75. R ３ 75. The compound of claim 74, wherein is H.

76. R ３ is C １ -C １０ 75. The compound of claim 74, which is alkyl.

77. 77. The compound of any one of claims 74-76, wherein L is selected from an acid labile linker, a hydrolytically labile linker, an enzymatically cleavable linker, a reduction labile linker, a self-immolative linker, and a non-cleavable linker.

78. 77. The compound of any one of claims 74-76, wherein L comprises one or more peptides, glucuronides, succinimide thioethers, polyethylene glycol (PEG) units, hydrazones, mal-caproyl units, dipeptide units, valine-citrulline units, or para-aminobenzyl (PAB) units.

79. 79. The compound of any one of claims 74 to 78, wherein L is at most 10 atoms in length, preferably at most 5 atoms in length.

80. L is -N(R ２ )-, -O-, -S-, -C(=NR ２ )-, -C(=O)-,C １－１０ Alkylene, C ２－１０ Alkenylene, C ３－１０ Alkynylene, C ４－１０ Cycloalkylene, C ６－１０ arylene, and combinations thereof; R ２ independently for each occurrence, H, C １－１０ Alkyl, C ２－１０ Alkenyl, C ３－１０ Alkynyl, C ３－１０ Cycloalkyl, C ６－１０ Aryl, C ２－９ heterocyclyl, or C ５－９ heteroaryl, optionally selected from -OH, -OR', =O, =S, -SH, -SR', -NH ２ , -NHR', -N(R') ２ , —NHCOR′, NR′COR′, halogen, —CN, —CO ２ H, -CO ２ R', -CHO, -COR', -CONH ２ , -CONHR', -CON(R') ２ , -NO ２ , -OP(O)(OH) ２ , -SO ３ H, -SO ３ R', -SOR', and -SO ２ R' is substituted with one or more substituents selected from, １－１０ Alkyl or C ３－１０ 80. The compound of any one of claims 74 to 79, which is cycloalkyl.

81. L is one or more -N(R ２ )-, R ２ is, independently for each occurrence, H or C １－１０ 81. The compound of claim 80, which is alkyl, preferably methyl.

82. 82. The compound of claim 80 or 81, wherein L contains one or more -C(=O)-.

83. L is one or more C １－１０ 83. The compound of any one of claims 80 to 82, comprising an alkylene.

84. R ３ together with the L moiety, the nitrogen atom to which they are attached and C ２－９ 84. The compound according to any one of claims 74 or 77 to 83, which forms a heterocycle.

85. Said C ２－９ 85. The compound of claim 84, wherein the heterocycle is a 5-, 6-, or 7-membered heterocycle.

86. Said C ２－９ 86. The compound of claim 85, wherein the heterocycle is a 6-membered heterocycle, preferably selected from piperazine, hexahydropyrimidine, hexahydropyridazine, 1,2,3-triazinane, 1,2,4-triazinane, and 1,3,5-triazinane.

87. 87. The compound of claim 86, wherein the six-membered heterocycle is piperazine.

88. Said C ２－９ 86. The compound of claim 85, wherein the heterocycle is a 5-membered heterocycle, preferably selected from pyrrolidine, pyrazolidine and imidazoline.

89. The compound is a compound of formula IIa: 【Chemistry 5】 R １ H, C １－１０ Alkyl, C ２－１０ Alkenyl, C ３－１０ Alkynyl, C ３－１０ Cycloalkyl, C ６－１０ Aryl, C ２－９ heterocyclyl, or C ５－９ heteroaryl, optionally selected from -OH, -OR', =O, =S, -SH, -SR', -NH ２ , -NHR', -N(R') ２ , —NHCOR′, —NR′COR′, halogen, —CN, —CO ２ H, -CO ２ R', -CHO, -COR', -CONH ２ , -CONHR', -CON(R') ２ , -NO ２ , -OP(O)(OH) ２ , -SO ３ H, -SO ３ R', -SOR', and -SO ２ R' is substituted with one or more substituents selected from, １－１０ Alkyl or C ３－１０ is cycloalkyl, or a pharmaceutically acceptable salt thereof.

90. R １ 90. The compound of claim 89, wherein is H.

91. R １ is C １ -C １０ 90. The compound of claim 89, which is alkyl.

92. R １ 92. The compound of claim 91, wherein is methyl.

93. 1. A compound, wherein the compound is a compound of formula III: 【Chemistry 6】 R ３ H, C １－１０ Alkyl, C ２－１０ Alkenyl, C ３－１０ Alkynyl, C ３－１０ Cycloalkyl, C ６－１０ Aryl, C ２－９ heterocyclyl, or C ５－９ heteroaryl, optionally selected from -OH, -OR', =O, =S, -SH, -SR', -NH ２ , -NHR', -N(R') ２ , —NHCOR′, —NR′COR′, halogen, —CN, —CO ２ H, -CO ２ R', -CHO, -COR', -CONH ２ , -CONHR', -CON(R') ２ , -NO ２ , -OP(O)(OH) ２ , -SO ３ H, -SO ３ R', -SOR', and -SO ２ R' is substituted with one or more substituents selected from, １－１０ Alkyl or C ３－１０ is cycloalkyl; or R ３ together with the L moiety, the nitrogen atom to which they are attached and C ２－９ forming a heterocyclic ring; L is a bivalent linker, preferably up to 20 atoms in length; Mが ２２５ Ac, ５１ Cr, ６６ Ga, ６７ Ga, ６８ Ga[ １８ F]Al,F、 １１１ In, １１３ｍ In, ５２ｍ Mn, ９９ｍ Tc、 １８６ Re, １８８ Re, １３９ No, １４０ No, １７５ Yb、 １７９ Yb、 １５３ Sm, １７７ｍ Sn, １６６ Hello, ８６ Y、 ８８ Y、 ９０ Y、 １４９ Pm, １６５ Yes, １６９ Er, １７７ Lu, ５２ Fe, ４３ Sc, ４４ Sc, ４６ Sc, ４７ Sc, １４２ Pr, １５７ Gdf, １５９ Gdf, ２１２ Yes, ２１３ Yes, ７２ As, ７７ As, ９７ Ru, １０９ Pd, １０５ Rh, １０１ｍ Rh, １１９ Sb, １９７ Hg, １５１ Eu, １５３ Eu, １６９ Eu, ２０１ Tl、 １４９ T﹂, １５２ T﹂, １５５ T﹂, １６１ T﹂, ２０３ Pb, ２１２ Pb, １５１ Pm, １５３ Pm, １４２ Pr, １４３ Pr, ５５ Yes, ６０ Cu, ６１ Cu, ６２ Cu, ６４ Cu, ６７ Cu, ６２ Zn, １８８ Re, １９８ Au, １９９ Au, ２２７ Th, １１１ Ag, １９９ Ag, ２１１ At, ２２３ Ra, ８８ Zr and ８９ Zr, preferably ６１ Cu, ６２ Cu, ６４ Cu and ６７ Cu; or a pharmaceutically acceptable salt thereof.

94. R ３ 94. The compound of claim 93, wherein is H.

95. R ３ is C １ -C １０ 94. The compound of claim 93, which is alkyl.

96. 96. The compound of any one of claims 93-95, wherein L is selected from an acid labile linker, a hydrolytically labile linker, an enzymatically cleavable linker, a reduction labile linker, a self-immolative linker, and a non-cleavable linker.

97. 96. The compound of any one of claims 93-95, wherein L comprises one or more peptides, glucuronides, succinimide thioethers, polyethylene glycol (PEG) units, hydrazones, mal-caproyl units, dipeptide units, valine-citrulline units, or para-aminobenzyl (PAB) units.

98. 96. The compound of any one of claims 93 to 95, wherein L is at most 10 atoms in length, preferably at most 5 atoms in length.

99. L is -N(R ２ )-, -O-, -S-, -C(=NR ２ )-, -C(=O)-,C １－１０ Alkylene, C ２－１０ Alkenylene, C ３－１０ Alkynylene, C ４－１０ Cycloalkylene, C ６－１０ arylene, and combinations thereof; ２ independently for each occurrence, H, C １－１０ Alkyl, C ２－１０ Alkenyl, C ３－１０ Alkynyl, C ３－１０ Cycloalkyl, C ６－１０ Aryl, C ２－９ heterocyclyl, or C ５－９ heteroaryl, optionally selected from -OH, -OR', =O, =S, -SH, -SR', -NH ２ , -NHR', -N(R') ２ , —NHCOR′, NR′COR′, halogen, —CN, —CO ２ H, -CO ２ R', -CHO, -COR', -CONH ２ , -CONHR', -CON(R') ２ , -NO ２ , -OP(O)(OH) ２ , -SO ３ H, -SO ３ R', -SOR', and -SO ２ R' is substituted with one or more substituents selected from, １－１０ Alkyl or C ３－１０ 96. The compound of any one of claims 93 to 95, which is cycloalkyl.

100. L is one or more -N(R ２ )-, R ２ is, independently for each occurrence, H or C １－１０ 100. The compound of claim 99, which is alkyl, preferably methyl.

101. 101. The compound of claim 99 or 100, wherein L contains one or more -C(=O)-.

102. L is one or more C １－１０ 102. The compound of any one of claims 99 to 101, comprising an alkylene.

103. R ３ together with the L moiety, the nitrogen atom to which they are attached and C ２－９ 103. The compound of any one of claims 93 or 96 to 102, which forms a heterocycle.

104. Said C ２－９ 104. The compound of claim 103, wherein the heterocycle is a 5-, 6-, or 7-membered heterocycle.

105. Said C ２－９ 104. The compound of claim 103, wherein the heterocycle is a 6-membered heterocycle, preferably selected from piperazine, hexahydropyrimidine, hexahydropyridazine, 1,2,3-triazinane, 1,2,4-triazinane, and 1,3,5-triazinane.

106. 106. The compound of claim 105, wherein the six-membered heterocycle is piperazine.

107. Said C ２－９ 104. The compound of claim 103, wherein the heterocycle is a 5-membered heterocycle, preferably selected from pyrrolidine, pyrazolidine and imidazoline.

108. M ６１ Cu, ６２ Cu, ６４ Cu and ６７ 108. The compound of any one of claims 93 to 107, wherein the compound is selected from Cu.

109. The compound is of formula IIIa: 【Chemistry 7】 R １ H, C １－１０ Alkyl, C ２－１０ Alkenyl, C ３－１０ Alkynyl, C ３－１０ Cycloalkyl, C ６－１０ Aryl, C ２－９ heterocyclyl, or C ５－９ heteroaryl, optionally selected from -OH, -OR', =O, =S, -SH, -SR', -NH ２ , -NHR', -N(R') ２ , —NHCOR′, —NR′COR′, halogen, —CN, —CO ２ H, -CO ２ R', -CHO, -COR', -CONH ２ , -CONHR', -CON(R') ２ , -NO ２ , -OP(O)(OH) ２ , -SO ３ H, -SO ３ R', -SOR', and -SO ２ R' is substituted with one or more substituents selected from, １－１０ Alkyl or C ３－１０ is cycloalkyl, or a pharmaceutically acceptable salt thereof.

110. R １ is H.

111. R １ is C １ -C １０ 110. The compound of claim 109, which is alkyl.

112. R １ is methyl.

113. A pharmaceutical composition comprising a compound according to any one of claims 1 to 112 and one or more pharmaceutically acceptable excipients.

114. 13. A pharmaceutical composition comprising a compound of any one of claims 1-11, 15-20, 22-41, 45-51, 73, or 93-112, wherein the composition is characterized by one or more of: (i) a molar radioactivity of 3 MBq / nmol or greater; (ii) a radiochemical purity of 91% or greater; (iii) a radioactivity concentration of 8 MBq / mL or greater; and (iv) a radionuclide purity of the compound at the end of synthesis (EoB+2 hours) of 95% or greater.

115. 1. A method for generating one or more images of an object, comprising: administering to the subject an effective amount of a compound comprising a radionuclide according to any one of claims 1 to 11, 15 to 20, 22 to 43, 73, or 93 to 112, or a pharmaceutical composition comprising an effective amount of a compound comprising a radionuclide according to any one of claims 1 to 11, 15 to 20, 22 to 43, 73, or 93 to 112; generating one or more images of at least a portion of the subject's body; A method comprising:

116. 116. The method of claim 115, wherein a compound of claim 25 is administered to the subject.

117. 117. The method of claim 115 or 116, wherein the image is generated using positron emission tomography (PET), PET-computed tomography (PET-CT), or single photon emission computed tomography (SPECT).

118. 118. The method of any one of claims 115 to 117, further comprising determining the presence or absence of disease in the subject based on the presence or absence of localization of the radionuclide in the one or more images of the subject's body.

119. 119. The method of claim 118, wherein if the subject is determined to have a disease, the method further comprises administering to the subject a therapeutically effective amount of the compound of claim 26.

120. 120. The method of claim 119, wherein the disease is selected from cancer, an inflammatory disease, an infectious disease, and an immune disease.

121. 121. The method of claim 120, wherein the disease is cancer, and the cancer is selected from breast cancer (e.g., triple-negative breast cancer), pancreatic cancer, small intestine cancer, colon cancer, gastric cancer, rectal cancer, lung cancer (e.g., non-small cell lung cancer), head and neck cancer, ovarian cancer, hepatocellular carcinoma, epithelial cancer, esophageal cancer, hypopharyngeal cancer, nasopharyngeal carcinoma, laryngeal cancer, myeloma cells, bladder cancer, cholangiocarcinoma, clear cell renal carcinoma, neuroendocrine tumors, oncogenetic osteomalacia, sarcoma, CUP (cancer of unknown primary), thymic carcinoma, desmoid tumor, glioma, astrocytoma, cervical cancer, and prostate cancer.

122. 121. The method of claim 120, wherein the disease is selected from cardiovascular disease, liver fibrosis and cirrhosis, arthropathy, IgG4-related disease, pulmonary fibrosis and interstitial lung disease, Crohn's disease, tuberculosis, sarcoidosis, and periprosthetic joint infections.

123. 1. A method for detecting a disease in a subject, comprising: administering to the subject an effective amount of a compound comprising a radionuclide according to any one of claims 1 to 11, 15 to 20, 22 to 43, 73, or 93 to 112, or a pharmaceutical composition comprising an effective amount of a compound comprising a radionuclide according to any one of claims 1 to 11, 15 to 20, 22 to 43, 73, or 93 to 112; detecting said localization of said radionuclide; determining the presence or absence of the disease based on the presence or absence of the localization; A method comprising:

124. 124. The method of claim 123, wherein said localization is detected using positron emission tomography (PET), PET-computed tomography (PET-CT), or single photon emission computed tomography (SPECT).

125. 125. The method of claim 123 or 124, wherein the disease is selected from cancer, an inflammatory disease, an infectious disease, and an immune disease.

126. 126. The method of claim 125, wherein the disease is cancer, and the cancer is selected from breast cancer (e.g., triple-negative breast cancer), pancreatic cancer, small intestine cancer, colon cancer, gastric cancer, rectal cancer, lung cancer (e.g., non-small cell lung cancer), head and neck cancer, ovarian cancer, hepatocellular carcinoma, epithelial cancer, esophageal cancer, hypopharyngeal cancer, nasopharyngeal carcinoma, laryngeal cancer, myeloma cells, bladder cancer, cholangiocarcinoma, clear cell renal carcinoma, neuroendocrine tumor, oncogenetic osteomalacia, sarcoma, CUP (cancer of unknown primary), thymic carcinoma, desmoid tumor, glioma, astrocytoma, cervical cancer, and prostate cancer.

127. 127. The method of claim 126, wherein the disease is selected from cardiovascular disease, liver fibrosis and cirrhosis, joint disorders (e.g., rheumatoid arthritis), IgG4-related disease, pulmonary fibrosis and interstitial lung disease, Crohn's disease, tuberculosis, sarcoidosis, and periprosthetic joint infections.

128. 1. A method for determining the effectiveness of cancer treatment in a subject suffering from cancer, comprising: administering to said subject at earlier and later time points an effective amount of a compound comprising a radionuclide according to any one of claims 1 to 11, 15 to 20, 22 to 43, 73 or 93 to 112, or a pharmaceutical composition comprising an effective amount of a compound comprising a radionuclide according to any one of claims 1 to 11, 15 to 20, 22 to 43, 73 or 93 to 112; detecting said localization of said radionuclide at both said earlier and said later time points; determining the efficacy of the cancer treatment by comparing the amount of localization at the later time point with the amount of localization at the earlier time point; A method comprising:

129. 129. The method of claim 128, wherein the localization of the compound is detected using positron emission tomography (PET), PET-computed tomography (PET-CT), or single photon emission computed tomography (SPECT).

130. 130. The method of claim 128 or 129, wherein the earlier time point is before initiating the cancer treatment and the later time point is at least two weeks after initiating the cancer treatment.

131. 131. The method of any one of claims 128 to 130, wherein the cancer is selected from breast cancer (e.g., triple-negative breast cancer), pancreatic cancer, small intestine cancer, colon cancer, gastric cancer, rectal cancer, lung cancer (e.g., non-small cell lung cancer), head and neck cancer, ovarian cancer, hepatocellular carcinoma, epithelial cancer, esophageal cancer, hypopharyngeal cancer, nasopharyngeal carcinoma, laryngeal cancer, myeloma cells, bladder cancer, cholangiocarcinoma, clear cell renal carcinoma, neuroendocrine tumors, oncogenetic osteomalacia, sarcoma, CUP (cancer of unknown primary), thymic carcinoma, desmoid tumor, glioma, astrocytoma, cervical cancer, and prostate cancer.

132. 10. A method of treating a disease in a patient in need thereof, comprising administering to the patient an effective amount of a compound of any one of claims 1-11, 15-20, 22-29, 44-65, 69-73, or 93-112, or a pharmaceutical composition comprising a compound of any one of claims 1-11, 15-20, 22-29, 44-65, 69-73, or 93-112.

133. 133. The method of claim 132, wherein the disease is selected from cancer, an inflammatory disease, an infectious disease, and an immune disease.

134. 134. The method of claim 133, wherein the disease is cancer and is selected from breast cancer (preferably triple-negative breast cancer), pancreatic cancer, small intestine cancer, colon cancer, gastric cancer, rectal cancer, lung cancer (preferably non-small cell lung cancer), head and neck cancer, ovarian cancer, hepatocellular carcinoma, epithelial cancer, esophageal cancer, hypopharyngeal cancer, nasopharyngeal carcinoma, laryngeal cancer, myeloma cells, bladder cancer, cholangiocarcinoma, clear cell renal carcinoma, neuroendocrine tumors, oncogenetic osteomalacia, sarcoma, CUP (cancer of unknown primary), thymic carcinoma, desmoid tumor, glioma, astrocytoma, cervical cancer, and prostate cancer.

135. 133. The method of claim 132, wherein the disease is selected from cardiovascular disease, liver fibrosis and cirrhosis, joint disorders (e.g., rheumatoid arthritis), IgG4-related disease, pulmonary fibrosis and interstitial lung disease, Crohn's disease, tuberculosis, sarcoidosis, and periprosthetic joint infections.

136. A theranostic method, comprising: (a) a composition according to any one of claims 25, 38, 70, or 73; ６１ an effective amount of a first compound comprising a Cu radionuclide, or a compound according to any one of claims 25, 38, 70, 73, or 93-112; ６１ administering to a subject a pharmaceutical composition comprising an effective amount of a first compound comprising a Cu radionuclide, optionally wherein said radionuclide is ６１ Cu or *Cu ６１ Cu or M is ６１ Cu; and (b) generating one or more images of the subject (e.g., of a particular region or portion of the subject's body); (c) any one of claims 26, 48, 70, 73, or 93 to 112 ６７ an effective amount of a second compound comprising a Cu radionuclide, or a compound according to any one of claims 26, 48, 70, or 73. ６７ administering to said subject a pharmaceutical composition comprising an effective amount of a second compound comprising a Cu radionuclide, wherein optionally said radionuclide is ６７ Cu or *Cu ６７ Cu or M is ６７ Cu, and said first and second compounds of steps (a) and (c) differ only in the identity of the radioisotope. A method comprising:

137. of the first compound in the body of the subject. ６１ 137. The method of claim 136, further comprising determining the presence or absence of disease in the subject via the one or more images of the subject based on the presence or absence of localization of Cu radionuclides.

138. A theranostic method, comprising: (a) any one of claims 25, 38, 70, 73, or 93 to 112 ６１ an effective amount of a first compound comprising a Cu radionuclide, or a compound according to any one of claims 25, 38, 70, or 73; ６１ administering to said subject a pharmaceutical composition comprising an effective amount of a first compound comprising a Cu radionuclide, wherein optionally said radionuclide is ６１ Cu or *Cu ６１ Cu or M is ６１ Cu; (b) detecting the presence of the first compound in the subject's body via the one or more images of the subject. ６１ determining the presence or absence of a disease in the subject based on the presence or absence of localization of Cu radionuclides; (c) if the presence of a disease in the subject is determined, ６７ an effective amount of a second compound comprising a Cu radionuclide, or a compound according to any one of claims 26, 48, 70, or 73. ６７ administering to said subject a pharmaceutical composition comprising an effective amount of a second compound comprising a Cu radionuclide, wherein optionally said radionuclide is ６７ Cu or *Cu ６７ Cu or M is ６７ Cu; and Including, The method, wherein said first and second compounds of steps (a) and (c) differ only in the identity of the radioisotope.

139. (a) the first compound is ６１ [Cu]Cu-NODAGA-1, and said second compound is ６７ [Cu]Cu-NODAGA-1, (b) the first compound ６１ [Cu]Cu-NODAGA-2, and said second compound is ６７ [Cu]Cu-NODAGA-2, (c) the first compound ６１ [Cu]Cu-NODAGA-3, and the second compound is ６７ [Cu]Cu-NODAGA-3, (d) the first compound ６１ [Cu]Cu-NODAGA-4, and the second compound is ６７ [Cu]Cu-NODAGA-4, or (e) the first compound ６１ [Cu]Cu-NODAGA-FAPI-46, and said second compound is ６７ [Cu]Cu-NODAGA-FAPI-46, 139. The method of any one of claims 136 to 138.

140. 115. The pharmaceutical composition according to claim 113 or 114, having a pH of 4 to 7, preferably 5 to 7, more preferably 6 to 7.

Images