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WO2025217220A1 - Conjugués de dendrimères et leurs procédés d'utilisation - Google Patents

Conjugués de dendrimères et leurs procédés d'utilisation

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Publication number
WO2025217220A1
WO2025217220A1 PCT/US2025/023748 US2025023748W WO2025217220A1 WO 2025217220 A1 WO2025217220 A1 WO 2025217220A1 US 2025023748 W US2025023748 W US 2025023748W WO 2025217220 A1 WO2025217220 A1 WO 2025217220A1
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WIPO (PCT)
Prior art keywords
dendrimer
dendrimer conjugate
formula
pharmaceutically acceptable
acceptable salt
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Pending
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PCT/US2025/023748
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English (en)
Inventor
Jeffrey L. Cleland
Rishi SHARMA
Jiazhong Zhang
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Ashvattha Therapeutics Inc
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Ashvattha Therapeutics Inc
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Publication of WO2025217220A1 publication Critical patent/WO2025217220A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G83/00—Macromolecular compounds not provided for in groups C08G2/00 - C08G81/00
    • C08G83/002—Dendritic macromolecules
    • C08G83/003—Dendrimers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
    • A61K49/08—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
    • A61K49/08—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier
    • A61K49/10—Organic compounds
    • A61K49/12—Macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/06—Macromolecular compounds, carriers being organic macromolecular compounds, i.e. organic oligomeric, polymeric, dendrimeric molecules
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G83/00—Macromolecular compounds not provided for in groups C08G2/00 - C08G81/00
    • C08G83/002—Dendritic macromolecules
    • C08G83/003—Dendrimers
    • C08G83/004—After treatment of dendrimers

Definitions

  • dendrimer conjugates As compared to traditional imaging to visualize the ultimate states of a disease, molecular imaging is expected to detect abnormalities with more precision in an early stage, in which the required molecular imaging agents play a key role. In addition to their use as imaging agents, radionuclides have been utilized in cancer therapy. However, selective targeting of such imaging and therapeutic agents to sites of interest remains challenging.
  • SUMMARY [003] Provided herein are dendrimer conjugates, or salts thereof, and compositions comprising the dendrimer conjugates. Also provided are methods of using the dendrimer conjugates and compositions described herein.
  • a compound of Formula (I′) is of Formula (I).
  • the dendrimer, D is a PAMAM dendrimer.
  • the dendrimer is a generation 4 PAMAM dendrimer.
  • R 1 is 18 F, 89 Zr, 90 Y, or 177 Lu.
  • the compound of Formula (I) is of the formula: , or a pharmaceutically acceptable salt thereof, wherein D is a generation 4 PAMAM dendrimer.
  • D is a generation 4 PAMAM dendrimer.
  • the compound of Formula (II) is of Formula (II′).
  • dendrimer conjugates of Formula (II): or a pharmaceutically acceptable salt thereof wherein D is a dendrimer, R 1 is a radionuclide or a chelator comprising a radionuclide, and R A , R B , L 1 , L 2 , m, n, and p are as defined herein.
  • the dendrimer, D is a PAMAM dendrimer.
  • the dendrimer is a generation 4 or 6 PAMAM dendrimer.
  • R A is: 2/156 13813260 some embodiments, R 1 is 18 F, 89 Zr, 90 Y, or 177 Lu.
  • R 1 is DOTA (e.g., chelated to 111 In or 90 Y) or NOTA (e.g., chelated to 64 Cu).
  • the dendrimer conjugate of Formula (II) is of the formula: , or 3/156 13813260 , or a pharmaceutically acceptable salt thereof.
  • compositions comprising a dendrimer conjugate disclosed herein, or a pharmaceutically acceptable salt thereof.
  • the composition further comprises a pharmaceutically acceptable excipient.
  • provided herein are methods of imaging a tissue in a subject, wherein the method comprises administering a dendrimer conjugate disclosed herein, or a pharmaceutically acceptable salt thereof, or composition disclosed herein to a subject; and obtaining an image representation of a tissue in the subject. Such methods are useful for diagnosing and ultimately treating diseases.
  • methods of treating cancer in a subject wherein the method comprises administering a dendrimer conjugate as disclosed herein, or a pharmaceutically acceptable salt thereof, or composition disclosed herein to a subject.
  • the cancer is brain cancer, breast cancer, ovarian cancer, uterine cancer, prostate cancer, testicular germ cell tumor, gastric cancer, esophagus cancer, lung cancer, liver cancer, renal cell cancer, or colon cancer.
  • FIG.1 shows representative PET/CT images from 2H, 24H, and 48H after injection of [ 64 Cu]Cu-V01NT3M2160 MBq/mg. Left: axial images sectioned at tumor. Middle: coronal image sectioned at kidney and tumor. Right: maximum intensity projection (MIP).
  • FIG.2 shows representative PET/CT images from 2H, 24H, and 48H after injection of [ 64 Cu]Cu-V01NT3M216 MBq/mg.
  • FIG.3 shows representative PET/CT images from 2H, 24H, and 48H after injection of [ 64 Cu]Cu-S08NT3M3200 MBq/mg. Left: axial images sectioned at tumor. Middle: coronal image sectioned at kidney and tumor.
  • FIG.4 shows representative PET/CT images from 2H, 24H, and 48H after injection of [ 64 Cu]Cu-S08NT3M320 MBq/mg. Left: axial images sectioned at tumor. Middle: coronal image sectioned at liver. Right: maximum intensity projection (MIP).
  • FIG.5 shows representative PET/CT images from 2H, 24H, and 48H after injection of [ 64 Cu]Cu-S08NT3M320 MBq/mg. Left: axial images sectioned at tumor. Middle: coronal image sectioned at kidney and tumor. Right: maximum intensity projection (MIP).
  • FIG.6 shows representative PET/CT images from 2H, 24H, and 48H after injection of [ 64 Cu]Cu-V01NT3M2160 MBq/mg.
  • FIG.7 shows representative PET/CT images from 2H, 24H, and 48H after injection of [ 64 Cu]Cu-S08NT3M3200 MBq/mg.
  • Middle coronal image sectioned at kidney.
  • FIG.8 shows representative PET/CT images from 2H, 24H, and 48H after injection of [ 64 Cu]Cu-V01NT3M2160 MBq/mg.
  • FIG.9 shows representative PET/CT images from 2H, 24H, and 48H after injection of [ 64 Cu]Cu-V01NT3M216 MBq/mg.
  • Middle coronal image sectioned at kidney and tumor.
  • FIG.10 shows representative PET/CT images from 2H, 24H, and 48H after injection of [ 64 Cu]Cu-S08NT3M3200 MBq/mg.
  • FIG.11 shows representative PET/CT images from 2H, 24H, and 48H after injection of [ 64 Cu]Cu-S08NT3M320 MBq/mg. Left: axial images sectioned at tumor. Middle: coronal image sectioned at liver.
  • MIP maximum intensity projection
  • FIG.12 shows representative PET/CT images from 2H, 24H, and 48H after injection of [ 64 Cu]Cu-S08NT3M320 MBq/mg.
  • FIG.13 shows representative PET/CT images from 2H, 24H, and 48H after injection of [ 64 Cu]Cu-V01NT3M2160 MBq/mg.
  • Middle coronal image sectioned at kidney.
  • FIG.14 shows representative PET/CT images from 2H, 24H, and 48H after injection of [ 64 Cu]Cu-S08NT3M3200 MBq/mg.
  • FIG.15 shows representative PET/CT images from 2H, 24H, and 48H after injection of [ 64 Cu]Cu-S08NT3M3200 MBq/mg. Left: axial images sectioned at tumor. Middle: coronal image sectioned at kidney and tumor. Right: maximum intensity projection (MIP).
  • FIG.16 shows representative PET/CT images from 2H, 24H, and 48H after injection of [ 64 Cu]Cu-S08NT3M320 MBq/mg. Left: axial images sectioned at tumor. Middle: coronal image sectioned at liver. Right: maximum intensity projection (MIP).
  • FIG.17 shows representative PET/CT images from 2H, 24H, and 48H after injection of [ 64 Cu]Cu-S08NT3M320 MBq/mg. Left: axial images sectioned at tumor. Middle: coronal image sectioned at kidney and tumor. Right: maximum intensity projection (MIP).
  • FIG.18 shows representative PET/CT images from 2H, 24H, and 48H after injection of [ 64 Cu]Cu-S08NT3M3200 MBq/mg.
  • Left axial images sectioned at bladder.
  • Middle coronal image sectioned at kidney.
  • Right maximum intensity projection (MIP).
  • FIGs.28A-28H show selected dendrimers of Formulae (II′) and/or (II).
  • FIG.28A shows a NOTA dendrimer.
  • FIG.28B shows a NODAGA dendrimer.
  • FIG.28C shows a MACROPA dendrimer.
  • FIG.28D shows a DOTA dendrimer comprising a bicyclic R B and 3 DOTA moieties.
  • FIG.28E shows another DOTA dendrimer comprising a 3 PEG linker, bicyclic R B , and 5 DOTA moieties.
  • FIG.28F shows yet another DOTA dendrimer comprising a 2 PEG linker, bicyclic R B , and 5 DOTA moieties.
  • FIG.28G shows another DOTA dendrimer comprising a quadricyclic R B and 5 DOTA moieties.
  • FIG.28H shows yet another DOTA dendrimer comprising a quadricyclic R B and 2 DOTA moieties.
  • FIGs.29A and 29B show example moieties to be incorporated into the dendrimers of Formulae (I′), (I), (II′), and/or (II).
  • FIG.29A shows an exemplary list of tetrazine functionalized chelators (i.e. ⁇ precursors to -RB-L2-R1 of Formulae (I′), (I), (II′), and (II)) that can be made through amide coupling or thiourea coupling.
  • the tetrazine moieties shown in FIG.29A may be reacted to ultimately form one of the polycyclic rings in R B .
  • FIG.29B shows exemplary R 1 of Formulae (I′) and (II′), pre-chelation to a radionuclide (i.e., resulting in Formulae (I) and (II) upon chelation).
  • the disclosure provides dendrimer conjugates comprising hydroxyl-terminated dendrimers conjugated to one or more radionuclides, compositions comprising such dendrimer conjugates, and uses thereof in methods of imaging and/or treating.
  • dendrimer conjugates of the disclosure selectively target activated microglia, sites of inflammation following systemic administration, and/or tumor-associated macrophages.
  • dendrimer conjugates of the disclosure can cross the impaired blood-brain barrier (BBB) and selectively target activated microglia and/or tumor- associated macrophages following systemic administration.
  • BBB blood-brain barrier
  • dendrimer conjugates of the disclosure provide stable PET imaging agents for non-invasive and specific imaging of a tissue.
  • dendrimer conjugates of the disclosure are therapeutically effective for treating neurological disorders, autoimmune disorders, and/or cancer.
  • the disclosure provides dendrimer conjugates comprising a hydroxyl- terminated dendrimer conjugated to a radionuclide, such as 18 F, 64 Cu, 89 Zr, 90 Y, 111 In, 177 Lu, 203 Pb, or 225 Ac, and methods of using the same for imaging a tissue in a subject.
  • a radionuclide such as 18 F, 64 Cu, 89 Zr, 90 Y, 111 In, 177 Lu, 203 Pb, or 225 Ac
  • the disclosure provides methods of using dendrimer conjugates for diagnosing, detecting, and/or imaging one or more sites of inflammation in a subject.
  • the 7/156 13813260 disclosure provides methods of using dendrimer conjugates for diagnosing, detecting, and/or imaging one or more cancer cells in a subject.
  • the disclosure provides methods of using dendrimer conjugates for treating a cancer in a subject. Definitions [0040] Definitions of specific functional groups and chemical terms are described in more detail below. These and other exemplary substituents are described in more detail in the Detailed Description, Examples, and Claims. The present disclosure is not limited in any manner by the below exemplary listing of substituents.
  • alkyl encompasses, C1, C2, C3, C4, C5, C6, C1–6, C1–5, C1–4, C1–3, C1–2, C2–6, C2–5, C2–4, C2–3, C3–6, C3–5, C3–4, C4–6, C4–5, and C5–6 alkyl.
  • alkyl refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 20 carbon atoms (“C 1–20 alkyl”).
  • an alkyl group has 1 to 12 carbon atoms (“C1–12 alkyl”). In some embodiments, an alkyl group has 1 to 10 carbon atoms (“C 1–10 alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms (“C 1–9 alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“C1–8 alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“C1–7 alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“C1–6 alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C 1–5 alkyl”).
  • an alkyl group has 1 to 4 carbon atoms (“C1–4 alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“C1–3 alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“C 1–2 alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“C 1 alkyl”). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C 2-6 alkyl”).
  • C 1–6 alkyl groups include methyl (C1), ethyl (C2), propyl (C3) (e.g., n-propyl, isopropyl), butyl (C4) (e.g., n-butyl, tert-butyl, sec-butyl, isobutyl), pentyl (C 5 ) (e.g., n-pentyl, 3-pentanyl, amyl, neopentyl, 3-methyl-2-butanyl, tert-amyl), and hexyl (C 6 ) (e.g., n-hexyl).
  • C 1–6 alkyl groups include methyl (C1), ethyl (C2), propyl (C3) (e.g., n-propyl, isopropyl), butyl (C4) (e.g., n-butyl, tert-butyl, sec-butyl,
  • alkyl groups include n-heptyl (C7), n-octyl (C8), n-dodecyl (C12), and the like. Unless otherwise specified, each instance of an alkyl group is independently unsubstituted (an “unsubstituted alkyl”) or substituted (a “substituted alkyl”) with one or more substituents (e.g., halogen, such as F).
  • substituents e.g., halogen, such as F
  • the alkyl group is an unsubstituted C1–12 alkyl (such as unsubstituted C1–6 alkyl, e.g., ⁇ CH3 (Me), unsubstituted ethyl (Et), unsubstituted propyl (Pr, e.g., unsubstituted n-propyl (n-Pr), unsubstituted isopropyl (i-Pr)), unsubstituted butyl (Bu, 8/156 13813260 e.g., unsubstituted n-butyl (n-Bu), unsubstituted tert-butyl (tert-Bu or t-Bu), unsubstituted sec- butyl (sec-Bu or s-Bu), unsubstituted isobutyl (i-Bu)).
  • unsubstituted C1–12 alkyl such as unsubstituted C1–6 alky
  • the alkyl group is a substituted C1–12 alkyl (such as substituted C1–6 alkyl, e.g., –CH2F, –CHF2, –CF3, – CH 2 CH 2 F, –CH 2 CHF 2 , –CH 2 CF 3 , or benzyl (Bn)).
  • heteroalkyl refers to an alkyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (e.g., inserted between adjacent carbon atoms of) and/or placed at one or more terminal position(s) of the parent chain.
  • a heteroalkyl group refers to a saturated group having from 1 to 20 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC 1–20 alkyl”). In certain embodiments, a heteroalkyl group refers to a saturated group having from 1 to 12 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1–12 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 11 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1–11 alkyl”).
  • a heteroalkyl group is a saturated group having 1 to 10 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC 1–10 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 9 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC 1–9 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1–8 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 7 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1–7 alkyl”).
  • a heteroalkyl group is a saturated group having 1 to 6 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1–6 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms within the parent chain (“heteroC 1–5 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and 1or 2 heteroatoms within the parent chain (“heteroC1–4 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom within the parent chain (“heteroC 1–3 alkyl”).
  • a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom within the parent chain (“heteroC1–2 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom (“heteroC1 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 2 to 6 carbon atoms and 1 or 2 heteroatoms within the parent chain (“heteroC2-6 alkyl”). Unless otherwise specified, each instance of a heteroalkyl group is independently unsubstituted (an “unsubstituted heteroalkyl”) or substituted (a “substituted heteroalkyl”) with one or more substituents.
  • the heteroalkyl group is an unsubstituted heteroC 1–12 alkyl. In certain embodiments, the heteroalkyl group is a substituted heteroC1–12 alkyl.
  • alkenyl refers to a radical of a straight-chain or branched hydrocarbon group having from 1 to 20 carbon atoms and one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 double bonds). In some embodiments, an alkenyl group has 1 to 20 carbon atoms (“C1-20 alkenyl”). In some embodiments, an alkenyl group has 1 to 12 carbon atoms (“C1–12 alkenyl”).
  • an alkenyl group has 1 to 11 carbon atoms (“C 1–11 alkenyl”). In some embodiments, an alkenyl group has 1 to 10 carbon atoms (“C 1–10 alkenyl”). In some embodiments, an alkenyl group has 1 to 9 carbon atoms (“C1–9 alkenyl”). In some embodiments, an alkenyl group has 1 to 8 carbon atoms (“C 1–8 alkenyl”). In some embodiments, an alkenyl group has 1 to 7 carbon atoms (“C 1–7 alkenyl”). In some embodiments, an alkenyl group has 1 to 6 carbon atoms (“C1–6 alkenyl”).
  • an alkenyl group has 1 to 5 carbon atoms (“C1–5 alkenyl”). In some embodiments, an alkenyl group has 1 to 4 carbon atoms (“C 1–4 alkenyl”). In some embodiments, an alkenyl group has 1 to 3 carbon atoms (“C 1–3 alkenyl”). In some embodiments, an alkenyl group has 1 to 2 carbon atoms (“C1–2 alkenyl”). In some embodiments, an alkenyl group has 1 carbon atom (“C 1 alkenyl”). In some embodiments, the one or more carbon-carbon double bonds are internal (such as in 2-butenyl) or terminal (such as in 1-butenyl).
  • Examples of C1–4 alkenyl groups include methylidenyl (C1), ethenyl (C2), 1- propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like.
  • Examples of C 1–6 alkenyl groups include the aforementioned C 2-4 alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like.
  • each instance of an alkenyl group is independently unsubstituted (an “unsubstituted alkenyl”) or substituted (a “substituted alkenyl”) with one or more substituents.
  • the alkenyl group is an unsubstituted C1-20 alkenyl.
  • the alkenyl group is a substituted C 1-20 alkenyl.
  • heteroalkenyl refers to an alkenyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (e.g., inserted between adjacent carbon atoms of) and/or placed at one or more terminal position(s) of the parent chain.
  • a heteroalkenyl group refers to a group 10/156 13813260 having from 1 to 20 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC1–20 alkenyl”).
  • a heteroalkenyl group refers to a group having from 1 to 12 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC 1–12 alkenyl”). In certain embodiments, a heteroalkenyl group refers to a group having from 1 to 11 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC1–11 alkenyl”). In certain embodiments, a heteroalkenyl group refers to a group having from 1 to 10 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC 1–10 alkenyl”).
  • a heteroalkenyl group has 1 to 9 carbon atoms at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC 1–9 alkenyl”). In some embodiments, a heteroalkenyl group has 1 to 8 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC1–8 alkenyl”). In some embodiments, a heteroalkenyl group has 1 to 7 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC 1–7 alkenyl”).
  • a heteroalkenyl group has 1to 6 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC1–6 alkenyl”). In some embodiments, a heteroalkenyl group has 1 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“heteroC 1–5 alkenyl”). In some embodiments, a heteroalkenyl group has 1 to 4 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“heteroC1–4 alkenyl”).
  • a heteroalkenyl group has 1 to 3 carbon atoms, at least one double bond, and 1 heteroatom within the parent chain (“heteroC 1–3 alkenyl”). In some embodiments, a heteroalkenyl group has 1 to 2 carbon atoms, at least one double bond, and 1 heteroatom within the parent chain (“heteroC1–2 alkenyl”). In some embodiments, a heteroalkenyl group has 1 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“heteroC 1–6 alkenyl”).
  • each instance of a heteroalkenyl group is independently unsubstituted (an “unsubstituted heteroalkenyl”) or substituted (a “substituted heteroalkenyl”) with one or more substituents.
  • the heteroalkenyl group is an unsubstituted heteroC 1–20 alkenyl.
  • the heteroalkenyl group is a substituted heteroC1–20 alkenyl.
  • alkynyl refers to a radical of a straight-chain or branched hydrocarbon group having from 1 to 20 carbon atoms and one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 triple bonds) (“C1-20 alkynyl”). In some embodiments, an alkynyl group has 1 to 10 carbon atoms (“C1-10 alkynyl”). In some embodiments, an alkynyl group has 1 to 9 carbon atoms (“C 1-9 alkynyl”). In some embodiments, an alkynyl group has 1 to 8 carbon atoms (“C 1-8 11/156 13813260 alkynyl”).
  • an alkynyl group has 1 to 7 carbon atoms (“C 1-7 alkynyl”). In some embodiments, an alkynyl group has 1 to 6 carbon atoms (“C1-6 alkynyl”). In some embodiments, an alkynyl group has 1 to 5 carbon atoms (“C1-5 alkynyl”). In some embodiments, an alkynyl group has 1 to 4 carbon atoms (“C 1-4 alkynyl”). In some embodiments, an alkynyl group has 1 to 3 carbon atoms (“C1-3 alkynyl”). In some embodiments, an alkynyl group has 1 to 2 carbon atoms (“C1-2 alkynyl”).
  • an alkynyl group has 1 carbon atom (“C 1 alkynyl”).
  • the one or more carbon-carbon triple bonds are internal (such as in 2-butynyl) or terminal (such as in 1-butynyl).
  • Examples of C1-4 alkynyl groups include, without limitation, methylidynyl (C1), ethynyl (C 2 ), 1-propynyl (C 3 ), 2-propynyl (C 3 ), 1-butynyl (C 4 ), 2-butynyl (C 4 ), and the like.
  • C 1-6 alkenyl groups include the aforementioned C 2-4 alkynyl groups as well as pentynyl (C5), hexynyl (C6), and the like. Additional examples of alkynyl include heptynyl (C7), octynyl (C8), and the like. Unless otherwise specified, each instance of an alkynyl group is independently unsubstituted (an “unsubstituted alkynyl”) or substituted (a “substituted alkynyl”) with one or more substituents. In certain embodiments, the alkynyl group is an unsubstituted C1-20 alkynyl.
  • the alkynyl group is a substituted C1-20 alkynyl.
  • heteroalkynyl refers to an alkynyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (e.g., inserted between adjacent carbon atoms of) and/or placed at one or more terminal position(s) of the parent chain.
  • a heteroalkynyl group refers to a group having from 1 to 20 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC1–20 alkynyl”).
  • a heteroalkynyl group refers to a group having from 1 to 10 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC 1–10 alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 9 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC 1–9 alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 8 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC1–8 alkynyl”).
  • a heteroalkynyl group has 1 to 7 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC 1–7 alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 6 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC1–6 alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms 12/156 13813260 within the parent chain (“heteroC 1–5 alkynyl”).
  • a heteroalkynyl group has 1 to 4 carbon atoms, at least one triple bond, and 1or 2 heteroatoms within the parent chain (“heteroC1–4 alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 3 carbon atoms, at least one triple bond, and 1 heteroatom within the parent chain (“heteroC 1–3 alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 2 carbon atoms, at least one triple bond, and 1 heteroatom within the parent chain (“heteroC1–2 alkynyl”).
  • a heteroalkynyl group has 1 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain (“heteroC 1–6 alkynyl”). Unless otherwise specified, each instance of a heteroalkynyl group is independently unsubstituted (an “unsubstituted heteroalkynyl”) or substituted (a “substituted heteroalkynyl”) with one or more substituents. In certain embodiments, the heteroalkynyl group is an unsubstituted heteroC 1–20 alkynyl. In certain embodiments, the heteroalkynyl group is a substituted heteroC1–20 alkynyl.
  • carbocyclyl refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 14 ring carbon atoms (“C 3-14 carbocyclyl”) and zero heteroatoms in the non-aromatic ring system.
  • a carbocyclyl group has 3 to 14 ring carbon atoms (“C3-14 carbocyclyl”).
  • a carbocyclyl group has 3 to 13 ring carbon atoms (“C 3-13 carbocyclyl”).
  • a carbocyclyl group has 3 to 12 ring carbon atoms (“C 3-12 carbocyclyl”).
  • a carbocyclyl group has 3 to 11 ring carbon atoms (“C3-11 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 10 ring carbon atoms (“C3-10 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms (“C 3-8 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 7 ring carbon atoms (“C3-7 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (“C3-6 carbocyclyl”).
  • a carbocyclyl group has 4 to 6 ring carbon atoms (“C 4-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 6 ring carbon atoms (“C 5-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (“C5-10 carbocyclyl”).
  • Exemplary C3-6 carbocyclyl groups include cyclopropyl (C 3 ), cyclopropenyl (C 3 ), cyclobutyl (C 4 ), cyclobutenyl (C 4 ), cyclopentyl (C 5 ), cyclopentenyl (C 5 ), cyclohexyl (C 6 ), cyclohexenyl (C 6 ), cyclohexadienyl (C6), and the like.
  • Exemplary C3-8 carbocyclyl groups include the aforementioned C3-6 carbocyclyl groups as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C 7 ), cycloheptatrienyl (C 7 ), cyclooctyl (C 8 ), cyclooctenyl (C 8 ), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), and the like.
  • Exemplary C3-10 carbocyclyl groups include the aforementioned C3-8 carbocyclyl groups as well as cyclononyl (C 9 ), cyclononenyl (C 9 ), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C 9 ), 13/156 13813260 decahydronaphthalenyl (C 10 ), spiro[4.5]decanyl (C 10 ), and the like.
  • Exemplary C 3-8 carbocyclyl groups include the aforementioned C3-10 carbocyclyl groups as well as cycloundecyl (C11), spiro[5.5]undecanyl (C11), cyclododecyl (C12), cyclododecenyl (C12), cyclotridecane (C13), cyclotetradecane (C 14 ), and the like.
  • the carbocyclyl group is either monocyclic (“monocyclic carbocyclyl”) or polycyclic (e.g., containing a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) or tricyclic system (“tricyclic carbocyclyl”)) and, in some embodiments, are saturated or contain one or more carbon-carbon double or triple bonds.
  • Carbocyclyl also includes ring systems wherein the carbocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups wherein the point of attachment is on the carbocyclyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the carbocyclic ring system.
  • each instance of a carbocyclyl group is independently unsubstituted (an “unsubstituted carbocyclyl”) or substituted (a “substituted carbocyclyl”) with one or more substituents.
  • the carbocyclyl group is an unsubstituted C 3-14 carbocyclyl.
  • the carbocyclyl group is a substituted C3-14 carbocyclyl.
  • “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 14 ring carbon atoms (“C 3-14 cycloalkyl”).
  • a cycloalkyl group has 3 to 10 ring carbon atoms (“C3-10 cycloalkyl”).
  • a cycloalkyl group has 3 to 8 ring carbon atoms (“C3-8 cycloalkyl”).
  • a cycloalkyl group has 3 to 6 ring carbon atoms (“C 3-6 cycloalkyl”).
  • a cycloalkyl group has 4 to 6 ring carbon atoms (“C4-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms (“C5-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms (“C 5-10 cycloalkyl”). Examples of C 5-6 cycloalkyl groups include cyclopentyl (C 5 ) and cyclohexyl (C 5 ). Examples of C 3-6 cycloalkyl groups include the aforementioned C5-6 cycloalkyl groups as well as cyclopropyl (C3) and cyclobutyl (C 4 ).
  • C 3-8 cycloalkyl groups include the aforementioned C 3-6 cycloalkyl groups as well as cycloheptyl (C 7 ) and cyclooctyl (C 8 ).
  • each instance of a cycloalkyl group is independently unsubstituted (an “unsubstituted cycloalkyl”) or substituted (a “substituted cycloalkyl”) with one or more substituents.
  • the cycloalkyl group is an unsubstituted C 3-14 cycloalkyl.
  • the cycloalkyl group is a substituted C3-14 cycloalkyl.
  • 14/156 13813260 The term “heterocyclyl” or “heterocyclic” refers to a radical of a 3- to 14-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“3–14 membered heterocyclyl”). In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment is a carbon or nitrogen atom, as valency permits.
  • a heterocyclyl group is monocyclic (“monocyclic heterocyclyl”) or polycyclic (e.g., a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”) or tricyclic system (“tricyclic heterocyclyl”)), and, in some embodiments, is saturated or contains one or more carbon-carbon double or triple bonds.
  • heterocyclyl polycyclic ring systems include one or more heteroatoms in one or both rings.
  • Heterocyclyl also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system.
  • each instance of heterocyclyl is independently unsubstituted (an “unsubstituted heterocyclyl”) or substituted (a “substituted heterocyclyl”) with one or more substituents.
  • the heterocyclyl group is an unsubstituted 3–14 membered heterocyclyl.
  • the heterocyclyl group is a substituted 3–14 membered heterocyclyl.
  • the heterocyclyl is substituted or unsubstituted, 3- to 7-membered, monocyclic heterocyclyl, wherein 1, 2, or 3 atoms in the heterocyclic ring system are independently oxygen, nitrogen, or sulfur, as valency permits.
  • a heterocyclyl group is a 5–10 membered non-aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–10 membered heterocyclyl”).
  • a heterocyclyl group is a 5–8 membered non-aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–8 membered heterocyclyl”).
  • a heterocyclyl group is a 5–6 membered non-aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–6 membered heterocyclyl”).
  • the 5–6 membered heterocyclyl has 1–3 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5–6 membered heterocyclyl has 1–2 ring heteroatoms 15/156 13813260 selected from nitrogen, oxygen, and sulfur.
  • the 5–6 membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.
  • Exemplary 3-membered heterocyclyl groups containing 1 heteroatom include azirdinyl, oxiranyl, and thiiranyl.
  • Exemplary 4-membered heterocyclyl groups containing 1 heteroatom include azetidinyl, oxetanyl, and thietanyl.
  • Exemplary 5-membered heterocyclyl groups containing 1 heteroatom include tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione.
  • Exemplary 5-membered heterocyclyl groups containing 2 heteroatoms include dioxolanyl, oxathiolanyl and dithiolanyl.
  • Exemplary 5-membered heterocyclyl groups containing 3 heteroatoms include triazolinyl, oxadiazolinyl, and thiadiazolinyl.
  • Exemplary 6-membered heterocyclyl groups containing 1 heteroatom include piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl.
  • Exemplary 6-membered heterocyclyl groups containing 2 heteroatoms include piperazinyl, morpholinyl, dithianyl, and dioxanyl.
  • Exemplary 6- membered heterocyclyl groups containing 3 heteroatoms include triazinyl.
  • Exemplary 7- membered heterocyclyl groups containing 1 heteroatom include azepanyl, oxepanyl and thiepanyl.
  • Exemplary 8-membered heterocyclyl groups containing 1 heteroatom include azocanyl, oxecanyl and thiocanyl.
  • Exemplary bicyclic heterocyclyl groups include indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl, decahydronaphthyridinyl, decahydro-1,8-naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl, phthalimidyl, naphthalimidyl, chromanyl, chromenyl, 1H-benzo[e][1,4]di
  • aryl refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 p electrons shared in a cyclic array) having 6–14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C6-14 aryl”).
  • an aryl group has 6 ring carbon atoms (“C6 aryl”; e.g., phenyl).
  • an aryl group has 10 ring carbon atoms (“C 10 aryl”; e.g., naphthyl such as 1–naphthyl and 2-naphthyl).
  • an aryl group has 14 ring 16/156 13813260 carbon atoms (“C 14 aryl”; e.g., anthracyl).
  • Aryl also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system.
  • each instance of an aryl group is independently unsubstituted (an “unsubstituted aryl”) or substituted (a “substituted aryl”) with one or more substituents.
  • the aryl group is an unsubstituted C 6-14 aryl.
  • the aryl group is a substituted C 6-14 aryl.
  • heteroaryl refers to a radical of a 5-14 membered monocyclic or polycyclic (e.g., bicyclic, tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 p electrons shared in a cyclic array) having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-14 membered heteroaryl”).
  • the point of attachment is a carbon or nitrogen atom, as valency permits.
  • heteroaryl polycyclic ring systems include one or more heteroatoms in one or both rings.
  • “Heteroaryl” includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heteroaryl ring system.
  • Heteroaryl also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused polycyclic (aryl/heteroaryl) ring system.
  • Polycyclic heteroaryl groups wherein one ring does not contain a heteroatom e.g., indolyl, quinolinyl, carbazolyl, and the like
  • the point of attachment is on either ring, e.g., either the ring bearing a heteroatom (e.g., 2- indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl).
  • the heteroaryl is substituted or unsubstituted, 5- or 6-membered, monocyclic heteroaryl, wherein 1, 2, 3, or 4 atoms in the heteroaryl ring system are independently oxygen, nitrogen, or sulfur.
  • the heteroaryl is substituted or unsubstituted, 9- or 10-membered, bicyclic heteroaryl, wherein 1, 2, 3, or 4 atoms in the heteroaryl ring system are independently oxygen, nitrogen, or sulfur.
  • “Heterobiaryl” refers to an instance of two aryl rings being fused together, wherein at least one of the aryl rings is heteroaryl. 17/156 13813260 [0055]
  • a heteroaryl group is a 5-10 membered aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heteroaryl”).
  • a heteroaryl group is a 5-8 membered aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heteroaryl”).
  • a heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heteroaryl”).
  • the 5-6 membered heteroaryl has 1–3 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5-6 membered heteroaryl has 1–2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each instance of a heteroaryl group is independently unsubstituted (an “unsubstituted heteroaryl”) or substituted (a “substituted heteroaryl”) with one or more substituents. In certain embodiments, the heteroaryl group is an unsubstituted 5-14 membered heteroaryl. In certain embodiments, the heteroaryl group is a substituted 5-14 membered heteroaryl.
  • Exemplary 5-membered heteroaryl groups containing 1 heteroatom include pyrrolyl, furanyl, and thiophenyl.
  • Exemplary 5-membered heteroaryl groups containing 2 heteroatoms include imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl.
  • Exemplary 5- membered heteroaryl groups containing 3 heteroatoms include triazolyl, oxadiazolyl, and thiadiazolyl.
  • Exemplary 5-membered heteroaryl groups containing 4 heteroatoms include tetrazolyl.
  • Exemplary 6-membered heteroaryl groups containing 1 heteroatom include pyridinyl.
  • Exemplary 6-membered heteroaryl groups containing 2 heteroatoms include pyridazinyl, pyrimidinyl, and pyrazinyl.
  • Exemplary 6-membered heteroaryl groups containing 3 or 4 heteroatoms include triazinyl and tetrazinyl, respectively.
  • Exemplary 7-membered heteroaryl groups containing 1 heteroatom include azepinyl, oxepinyl, and thiepinyl.
  • Exemplary 5,6-bicyclic heteroaryl groups include indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl.
  • Exemplary 6,6-bicyclic heteroaryl groups include naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and 18/156 13813260 quinazolinyl.
  • Exemplary tricyclic heteroaryl groups include phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl, and phenazinyl.
  • the term “unsaturated bond” refers to a double or triple bond.
  • the term “unsaturated” or “partially unsaturated” refers to a moiety that includes at least one double or triple bond. [0059] The term “saturated” or “fully saturated” refers to a moiety that does not contain a double or triple bond, e.g., the moiety only contains single bonds.
  • alkylene is the divalent moiety of alkyl
  • alkenylene is the divalent moiety of alkenyl
  • alkynylene is the divalent moiety of alkynyl
  • heteroalkylene is the divalent moiety of heteroalkyl
  • heteroalkenylene is the divalent moiety of heteroalkenyl
  • heteroalkynylene is the divalent moiety of heteroalkynyl
  • carbocyclylene is the divalent moiety of carbocyclyl
  • heterocyclylene is the divalent moiety of heterocyclyl
  • arylene is the divalent moiety of aryl
  • heteroarylene is the divalent moiety of heteroaryl.
  • a group is optionally substituted unless expressly provided otherwise.
  • the term “optionally substituted” refers to being substituted or unsubstituted.
  • alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted.
  • Optionally substituted refers to a group which is substituted or unsubstituted (e.g., “substituted” or “unsubstituted” alkyl, “substituted” or “unsubstituted” alkenyl, “substituted” or “unsubstituted” alkynyl, “substituted” or “unsubstituted” heteroalkyl, “substituted” or “unsubstituted” heteroalkenyl, “substituted” or “unsubstituted” heteroalkynyl, “substituted” or “unsubstituted” carbocyclyl, “substituted” or “unsubstituted” heterocyclyl, “substituted” or “unsubstituted” aryl or “substituted” or “unsubstituted” heteroaryl group).
  • substituted means that at least one hydrogen present on a group is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction.
  • 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 is either the same or different at each position.
  • substituted is contemplated to include substitution with all permissible substituents of organic compounds, and includes any of the substituents described herein that results in the formation of a stable compound.
  • the present disclosure contemplates any and all such combinations in order to arrive at a stable compound.
  • 19/156 13813260 heteroatoms such as nitrogen may have hydrogen substituents and/or any suitable substituent as described herein which satisfy the valencies of the heteroatoms and results in the formation of a stable moiety.
  • the disclosure is not limited in any manner by the exemplary substituents described herein.
  • a “counterion” or “anionic counterion” is a negatively charged group associated with a positively charged group in order to maintain electronic neutrality.
  • An anionic counterion may be monovalent (e.g., including one formal negative charge).
  • An anionic counterion may also be multivalent (e.g., including more than one formal negative charge), such as divalent or trivalent.
  • Exemplary counterions include halide ions (e.g., F – , Cl – , Br – , I – ), NO 3 – , ClO 4 – , OH – , H2PO4 – , HCO ⁇ 3 , HSO4 – , sulfonate ions (e.g., methansulfonate, trifluoromethanesulfonate, p– toluenesulfonate, benzenesulfonate, 10–camphor sulfonate, naphthalene–2–sulfonate, naphthalene–1–sulfonic acid–5–sulfonate, ethan–1–sulfonic acid–2–sulfonate, and the like), carboxylate ions (e.g., acetate, propanoate, benzoate, glycerate, lactate, tartrate, glycolate, gluconate, and the
  • Exemplary counterions which may be multivalent include CO 3 2 ⁇ , HPO 4 2 ⁇ , PO 4 3 ⁇ , B 4 O 7 2 ⁇ , SO 4 2 ⁇ , S 2 O 3 2 ⁇ , carboxylate anions (e.g., tartrate, citrate, fumarate, maleate, malate, malonate, gluconate, succinate, glutarate, adipate, pimelate, suberate, azelate, sebacate, salicylate, phthalates, aspartate, glutamate, and the like), and carboranes.
  • carboxylate anions e.g., tartrate, citrate, fumarate, maleate, malate, malonate, gluconate, succinate, glutarate, adipate, pimelate, suberate, azelate, sebacate, salicylate, phthalates, aspartate, glutamate, and the like
  • carboranes e.g., tartrate, citrate, fumarate, maleate, mal
  • Salts include ionic compounds that result from the neutralization reaction of an acid and a base.
  • a salt is composed of one or more cations (positively charged ions) and one or more anions (negative ions) so that the salt is electrically neutral (without a net charge).
  • Salts of the compounds of the present disclosure include those derived from inorganic and organic acids and bases.
  • acid addition salts are salts of 20/156 13813260 an amino group 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 using other methods known in the art such as ion exchange.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid
  • organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods known in the art such as ion exchange.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2–hydroxy–ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2–naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, per
  • 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, and the like.
  • Further salts include ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.
  • pharmaceutically acceptable salt refers to those salts which are, 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, and the like, and are 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, incorporated herein by reference.
  • 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, nontoxic acid addition salts are salts of an amino group 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 using other methods known in the art such as ion exchange.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid
  • organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods known in the art such as ion exchange.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, 21/156 13813260 lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamo
  • 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, and the like.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.
  • stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers”.
  • enantiomers When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible.
  • An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or ( ⁇ )-isomers respectively).
  • a chiral compound can exist as either individual enantiomer or as a mixture thereof.
  • a mixture containing equal proportions of the enantiomers is called a “racemic mixture”.
  • the term “tautomers” or “tautomeric” refers to two or more interconvertible compounds resulting from at least one formal migration of a hydrogen atom and at least one change in valency (e.g., a single bond to a double bond, a triple bond to a single bond, or vice versa). The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH. Tautomerizations (i.e., the reaction providing a tautomeric pair) may catalyzed by acid or base.
  • Exemplary tautomerizations include keto-to-enol, amide-to-imide, lactam-to-lactim, enamine-to-imine, and enamine-to-(a different enamine) tautomerizations.
  • isomers compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers”. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers”.
  • stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers”.
  • enantiomers When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible.
  • An enantiomer can be characterized by the absolute 22/156 13813260 configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or ( ⁇ )-isomers respectively).
  • a chiral compound can exist as either individual enantiomer or as a mixture thereof.
  • a mixture containing equal proportions of the enantiomers is called a “racemic mixture”.
  • the terms “composition” and “formulation” are used interchangeably.
  • a “subject” to which administration is contemplated refers to a human (i.e., male or female of any age group, e.g., pediatric subject (e.g., infant, child, or adolescent) or adult subject (e.g., young adult, middle-aged adult, or senior adult)) or non-human animal.
  • the non-human animal is a mammal (e.g., primate (e.g., cynomolgus monkey or rhesus monkey), commercially relevant mammal (e.g., cattle, pig, horse, sheep, goat, cat, or dog), or bird (e.g., commercially relevant bird, such as chicken, duck, goose, or turkey)).
  • the non-human animal is a fish, reptile, or amphibian.
  • the non-human animal may be a male or female at any stage of development.
  • the non-human animal may be a transgenic animal or genetically engineered animal.
  • patient refers to a human subject in need of treatment of a disease.
  • tissue refers to any biological tissue of a subject (including a group of cells, a body part, or an organ) or a part thereof, including blood and/or lymph vessels, which is the object to which a dendrimer conjugate and/or composition of the present disclosure is delivered.
  • a tissue may be an abnormal or unhealthy tissue, which may need to be treated or diagnosed.
  • a tissue may also be a normal or healthy tissue that is under a higher than normal risk of becoming abnormal or unhealthy, which may need to be prevented.
  • administer refers to implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing a compound described herein, or a composition thereof, in or on a subject.
  • treatment refers to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease described herein.
  • treatment may be administered after one or more signs or symptoms of the disease have developed or have been observed. In other embodiments, treatment may be administered in the absence of signs or symptoms of the disease.
  • treatment may be administered to a susceptible subject prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of exposure to a pathogen). Treatment may also be continued after symptoms have resolved, for example, to delay or prevent recurrence.
  • condition e.g., in light of a history of symptoms and/or in light of exposure to a pathogen. Treatment may also be continued after symptoms have resolved, for example, to delay or prevent recurrence.
  • condition e.g., in light of a history of symptoms and/or in light of exposure to a pathogen
  • Treatment may also be continued after symptoms have resolved, for example, to delay or prevent recurrence.
  • condition e.g., in light of a history of symptoms and/or in light of exposure to a pathogen
  • disorder are used interchangeably. 23/156 13813260
  • autoimmune disease and “autoimmune disorder” are used interchangeably herein and refer to a disease arising from an inappropriate immune response of the body of a subject against
  • autoimmune thyroiditis This may be restricted to certain organs (e.g., in autoimmune thyroiditis) or involve a particular tissue in different places (e.g., Goodpasture’s disease which may affect the basement membrane in both the lung and kidney).
  • the treatment of autoimmune diseases is typically with immunosuppression, e.g., medications which decrease the immune response.
  • Exemplary autoimmune diseases include, but are not limited to, glomerulonephritis, Goodpasture’s syndrome, necrotizing vasculitis, lymphadenitis, peri-arteritis nodosa, systemic lupus erythematosis, rheumatoid arthritis, psoriatic arthritis, psoriasis, ulcerative colitis, systemic sclerosis, dermatomyositis/polymyositis, anti-phospholipid antibody syndrome, scleroderma, pemphigus vulgaris, ANCA-associated vasculitis (e.g., Wegener’s granulomatosis, microscopic polyangiitis), uveitis, Sjogren’s syndrome, Crohn’s disease, Reiter’s syndrome, ankylosing spondylitis, Lyme disease, Guillain-Barré syndrome, Hashimoto’s thyroiditis, and cardiomyopathy.
  • glomerulonephritis
  • Neurodegenerative diseases refer to a type of neurological disease marked by the loss of nerve cells, including, but not limited to, Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, tauopathies (including frontotemporal dementia), and Huntington’s disease.
  • neurological diseases include, but are not limited to, headache, stupor and coma, dementia, seizure, sleep disorders, trauma, infections, neoplasms, neuro-ophthalmology, movement disorders, demyelinating diseases, spinal cord disorders, and disorders of peripheral nerves, muscle and neuromuscular junctions.
  • Addiction and mental illness include, but are not limited to, bipolar disorder and schizophrenia, are also included in the definition of neurological diseases.
  • neurological diseases include acquired epileptiform aphasia; acute disseminated encephalomyelitis; adrenoleukodystrophy; agenesis of the corpus callosum; agnosia; Aicardi syndrome; Alexander disease; Alpers’ disease; alternating hemiplegia; Alzheimer’s disease; amyotrophic lateral sclerosis; anencephaly; Angelman syndrome; angiomatosis; anoxia; aphasia; apraxia; arachnoid cysts; arachnoiditis; Arnold-Chiari malformation; arteriovenous 24/156 13813260 malformation; Asperger syndrome; ataxia telangiectasia; attention deficit hyperactivity disorder; autism; autonomic dysfunction; back pain; Batten disease; Behcet’s disease; Bell’s palsy; benign essential blepharospasm; benign focal; amyotrophy; benign intracranial hypertension; Binswanger’s disease; ble
  • inflammatory disease and “inflammatory condition” are used interchangeably herein, and refer to a disease or condition caused by, resulting from, or resulting in inflammation.
  • Inflammatory diseases and conditions include those diseases, disorders or conditions that are characterized by signs of pain (dolor, from the generation of noxious substances and the stimulation of nerves), heat (calor, from vasodilatation), redness (rubor, from vasodilatation and increased blood flow), swelling (tumor, from excessive inflow or restricted outflow of fluid), and/or loss of function (functio laesa, which can be partial or complete, temporary or permanent.
  • Inflammation takes on many forms and includes, but is not limited to, acute, adhesive, atrophic, catarrhal, chronic, cirrhotic, diffuse, disseminated, exudative, fibrinous, fibrosing, focal, granulomatous, hyperplastic, hypertrophic, interstitial, metastatic, necrotic, obliterative, parenchymatous, plastic, productive, proliferous, pseudomembranous, purulent, sclerosing, seroplastic, serous, simple, specific, subacute, suppurative, toxic, traumatic, and/or ulcerative inflammation.
  • inflammatory disease may also refer to a dysregulated inflammatory reaction that causes an exaggerated response by macrophages, granulocytes, and/or T-lymphocytes leading to abnormal tissue damage and/or cell death.
  • An inflammatory disease can be either an acute or chronic inflammatory condition and can result from infections or non-infectious causes.
  • Inflammatory diseases include, without limitation, atherosclerosis, arteriosclerosis, autoimmune disorders, multiple sclerosis, systemic lupus erythematosus, polymyalgia rheumatica (PMR), gouty arthritis, degenerative arthritis, tendonitis, bursitis, psoriasis, cystic fibrosis, arthrosteitis, rheumatoid arthritis, inflammatory arthritis, Sjogren’s syndrome, giant cell arteritis, progressive systemic sclerosis (scleroderma), ankylosing spondylitis, polymyositis, dermatomyositis, pemphigus, pemphigoid, diabetes (e.g., Type I), myasthenia gravis, Hashimoto’s thyroiditis, Graves’ disease, Goodpasture’s disease, mixed connective tissue disease, sclerosing cholangitis, inflammatory bowel disease, Crohn’s disease, ulcerative colitis, per
  • An ocular inflammatory disease includes, but is not limited to, post-surgical inflammation.
  • Additional exemplary inflammatory conditions include, but are not limited to, inflammation associated with acne, anemia (e.g., aplastic anemia, hemolytic autoimmune anemia), asthma, arteritis (e.g., polyarteritis, temporal arteritis, periarteritis nodosa, Takayasu’s arteritis), arthritis (e.g., crystalline arthritis, osteoarthritis, psoriatic arthritis, gouty arthritis, reactive arthritis, rheumatoid arthritis and Reiter’s arthritis), ankylosing spondylitis, amylosis, amyotrophic lateral sclerosis, autoimmune diseases, allergies or allergic reactions, atherosclerosis, bronchitis, bursitis, chronic prostatitis, conjunctivitis, Chagas disease, chronic obstructive pulmonary disease, cermatomyositis, diverticulitis,
  • the inflammatory disorder is selected from arthritis (e.g., rheumatoid arthritis), inflammatory bowel disease, inflammatory bowel syndrome, asthma, psoriasis, endometriosis, interstitial cystitis and prostatitis.
  • the inflammatory condition is an acute inflammatory condition (e.g., for example, inflammation resulting from infection).
  • the inflammatory condition is a chronic inflammatory condition (e.g., conditions resulting from asthma, arthritis and inflammatory bowel disease).
  • the compounds may also be useful in treating inflammation associated with trauma and non-inflammatory myalgia.
  • the compounds disclosed herein may also be useful in treating inflammation associated with cancer.
  • cancer refers to a class of diseases characterized by the development of abnormal cells that proliferate uncontrollably and have the ability to infiltrate and destroy normal body tissues. See e.g., Stedman’s Medical Dictionary, 25th ed.; Hensyl ed.; Williams & Wilkins: Philadelphia, 1990.
  • Exemplary cancers include, but are not limited to, acoustic neuroma; adenocarcinoma; adrenal gland cancer; anal cancer; angiosarcoma (e.g., lymphangiosarcoma, lymphangioendotheliosarcoma, hemangiosarcoma); appendix cancer; benign monoclonal gammopathy; biliary cancer (e.g., cholangiocarcinoma); bladder cancer; breast cancer (e.g., adenocarcinoma of the breast, papillary carcinoma of the breast, mammary cancer, medullary carcinoma of the breast); brain cancer (e.g., meningioma, glioblastomas, glioma (e.g., astrocytoma, oligodendroglioma), medulloblastoma); bronchus cancer; carcinoid tumor; cervical cancer (e.g., cervical adenocarcinoma); choriocar
  • Wilms tumor, renal cell carcinoma); liver cancer (e.g., hepatocellular cancer (HCC), malignant hepatoma); lung cancer (e.g., bronchogenic carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), adenocarcinoma of the lung); leiomyosarcoma (LMS); mastocytosis (e.g., systemic mastocytosis); muscle cancer; myelodysplastic syndrome (MDS); mesothelioma; myeloproliferative disorder (MPD) (e.g., polycythemia vera (PV), essential thrombocytosis (ET), agnogenic myeloid metaplasia (AMM) a.k.a.
  • HCC hepatocellular cancer
  • lung cancer e.g., bronchogenic carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), adenocarcinoma of the lung
  • myelofibrosis 30/156 13813260 MF
  • chronic idiopathic myelofibrosis chronic myelocytic leukemia (CML), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES)
  • neuroblastoma e.g., neurofibromatosis (NF) type 1 or type 2, schwannomatosis
  • neuroendocrine cancer e.g., gastroenteropancreatic neuroendoctrine tumor (GEP-NET), carcinoid tumor
  • osteosarcoma e.g.,bone cancer
  • ovarian cancer e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma
  • papillary adenocarcinoma pancreatic cancer (e.g., pancreatic andenocarcinoma, intraductal papillary mucinous neoplasm (IPMN), Islet cell tumors); penile
  • the bicyclic moiety drawn herein as: meant to also encompass the following non-fully oxidized forms: . 31/156 13813260
  • the polycyclic moiety drawn herein as: is meant to also encompass the following regioisomer: .
  • Dendrimer Conjugates of Formulae (I′) and (I) [0083]
  • D is a dendrimer
  • Z is substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted heteroalkylene, or substituted or unsubstituted heteroalkenylene
  • R 1 is a radionuclide or a chelator of a radionuclide
  • q is an integer from 0-50, inclusive
  • m is an integer from 16-4095, inclusive
  • n is an integer from 1-20, inclusive
  • p is an integer from 0-20, inclusive.
  • the compound of Formula (I′) is of Formula (I) (e.g., the chelator is chelating a radionuclide).
  • the chelator is chelating a radionuclide.
  • D is a dendrimer
  • 32/156 13813260 Z is substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted heteroalkylene, or substituted or unsubstituted heteroalkenylene
  • R 1 is a radionuclide or a chelator comprising a radionuclide
  • q is an integer from 0-50, inclusive
  • m is an integer from 16-4095, inclusive
  • n is an integer from 1-20, inclusive
  • p is an integer from 0-20, inclusive.
  • dendrimer conjugate refers to a dendrimer that comprises at least one agent, such as an active agent, imaging agent, or therapeutic agent described herein.
  • the dendrimer is conjugated to the at least one agent through a covalent or non- covalent linkage.
  • the dendrimer is conjugated to a chelator, which can chelate a radionuclide (i.e., an imaging agent).
  • the dendrimer is conjugated to the at least one agent through a chelator, such as a dendrimer conjugate of Formula (I), where R 1 is a chelator comprising a radionuclide.
  • a dendrimer refers to a compound having a molecular architecture with an interior core and layers (or “generations”) of repeating units which are attached to and extend from this interior core, each layer having one or more branching points, and the outermost generation having terminal functional groups.
  • terminal functional groups of a dendrimer include one or more hydroxyl groups, one or more amine groups, and/or one or more carboxyl groups.
  • the terminal functional groups of a dendrimer provide attachment sites through which the at least one agent is conjugated to form the dendrimer conjugate.
  • the at least one agent is conjugated to the dendrimer through an ether bond, an amide bond, or an ester bond formed by conjugation to a terminal functional group of the dendrimer. In some embodiments, the at least one agent is conjugated to the dendrimer through an ether bond or an amide bond. In some embodiments, the at least one agent is conjugated to the dendrimer through an ether bond. [0087] D is a dendrimer as described herein.
  • D is a polyamidoamine (PAMAM), polypropylamine (POPAM), polyethylenimine, polylysine, polyester, iptycene, aliphatic poly(ether), or an aromatic polyether dendrimer.
  • D is a polyamidoamine (PAMAM) dendrimer.
  • D is a polypropylamine (POPAM) dendrimer.
  • D is a polyethylenimine dendrimer.
  • D is a polylysine dendrimer.
  • D is a polyester dendrimer.
  • D is an iptycene dendrimer. In some 33/156 13813260 embodiments, D is an aliphatic poly(ether) dendrimer. In some embodiments, D is an aromatic polyether dendrimer. [0088] In some embodiments of Formula (I′) or (I), D is a generation 4, generation 5, generation 6, generation 7, or generation 8 dendrimer. In some embodiments, D is a generation 4 dendrimer. In some embodiments, D is a generation 5 dendrimer. In some embodiments, D is a generation 6 dendrimer. In some embodiments, D is a generation 7 dendrimer. In some embodiments, D is a generation 8 dendrimer.
  • D is a generation 4, generation 5, generation 6, generation 7, or generation 8 PAMAM dendrimer.
  • D is a generation 4 PAMAM dendrimer.
  • D is a generation 5 PAMAM dendrimer.
  • D is a generation 6 PAMAM dendrimer.
  • D is a generation 7 PAMAM dendrimer.
  • D is a generation 8 PAMAM dendrimer.
  • D is a generation 2, 3, 4, 5, 6, 7, 8, 9, or 10 PAMAM dendrimer, which has 16, 32, 64, 128, 256, 512, 1024, 2048, or 4096 terminal sites, respectively. Accordingly, in some embodiments, D is a generation 2, 3, 4, 5, 6, 7, 8, 9, or 10 PAMAM dendrimer, and m + n + p is 16, 32, 64, 128, 256, 512, 1024, 2048, or 4096, respectively. In some embodiments, D is a generation 4 PAMAM dendrimer, and m + n + p is 64. In some embodiments, D is a generation 5 PAMAM dendrimer, and m + n + p is 128.
  • R 1 is a radionuclide or a chelator of a radionuclide. In some embodiments, R 1 is a radionuclide. In some embodiments, R 1 is a chelator of a radionuclide (i.e., a chelator such as DOTA without the radionuclide present, but will chelate the radionuclide). [0092] In some embodiments of Formula (I), R 1 is a radionuclide or a chelator comprising a radionuclide.
  • R 1 is a radionuclide. In some embodiments, R 1 is a chelator comprising a radionuclide. [0093] In some embodiments of Formula (I′) or (I), the radionuclide is selected from the group consisting of 18 F, 47 Sc, 51 Cr, 51 Mn, 52 Fe, 60 Cu, 62 Cu, 64 Cu, 67 Cu, 67 Ga, 68 Ga, 72 As, 76 Br, 77 Br, 88 Y, 89 Zr, 90 Y, 94m Tc, 99m Tc, 97 Ru, 103 Ru, 105 Rh, 109 Pd, 110 In, 111 In , 117m Sn, 123 I, 124 I, 125 I, 131 I, 140 La, 141 Ce, 149 Pm, 153 Sm, 161 Tb, 165 Dy, 166 Dy, 166 Ho, 167 Tm, 168 Yb, 175 Yb, 177 Lu, 186 Re, 188 Re,
  • the radionuclide is 18 F, 44 Sc, 47 Sc, 51 Cr, 51 Mn, 52 Fe, 55 Co, 60 Cu, 61 Cu, 62 Cu, 64 Cu, 67 Cu, 67 Ga, 68 Ga, 72 As, 76 Br, 77 Br, 82 Rb, 86 Y, 88 Y, 89 Sr, 89 Zr, 90 Y, 94m Tc, 99m Tc, 97 Ru, 103 Ru, 34/156 13813260 105 Rh, 109 Pd, 110 In, 111 In , 117m Sn, 123 I, 124 I, 125 I, 131 I, 133 Xe, 140 La, 141 Ce, 149 Pm, 149 Tb, 152 Tb, 153 Sm, 161 Tb, 165 Dy, 166 Dy, 166 Ho, 167 Tm, 168 Yb, 175 Yb, 177 Lu, 186 Re, 188 Re, 198 Au, 199 Au, 201 Tl
  • the radionuclide is 18 F, 64 Cu, 90 Y, or 111 In, or ion thereof. In some embodiments, the radionuclide is 18 F, 64 Cu, 89 Zr, 90 Y, 111 In, 177 Lu, 203 Pb, or 225 Ac, or ion thereof. In some embodiments, the radionuclide is 18 F, 64 Cu, 90 Y, 111 In, 177 Lu, or 225 Ac, or ion thereof. In some embodiments, the radionuclide is 18 F, 64 Cu, or 177 Lu, or ion thereof.
  • the radionuclide is 11 C, 13 N, 18 F, 44 Sc, 51 Cr, 55 Co, 61 Cu, 64 Cu, 67 Ga, 67 Cu, 68 Ga, 82 Rb, 86 Y, 89 Zr, 89 Sr, 90 Y, ⁇ 99m ⁇ Tc, 111 In, ⁇ 117m ⁇ Sn, 123 I, 124 I, 125 I, 131 I, 133 Xe, 149 Tb, 152 Tb, 153 Sm, 161 Tb, 166 Ho, 166 Ho, 177 Lu, 186 Re, 188 Re, 201 Tl, 203 Pb, 212 Pb, 212 Bi, 213 Bi, 223 Ra, 225 Ac, or 227 Th, or ion thereof.
  • the radionuclide is 64 Cu, 90 Y, or 111 In, or ion thereof. In some embodiments, the radionuclide is 64 Cu, or ion thereof. In some embodiments, the radionuclide is 90 Y, or ion thereof. In some embodiments, the radionuclide is 111 In, or ion thereof. In some embodiments, the radionuclide is 18 F, or ion thereof. In some embodiments, the radionuclide is 89 Zr, or ion thereof. In some embodiments, the radionuclide is 90 Y, or ion thereof. In some embodiments, the radionuclide is 111 In, or ion thereof.
  • the radionuclide is 177 Lu, or ion thereof. In some embodiments, the radionuclide is 203 Pb, or ion thereof. In some embodiments, the radionuclide is 225 Ac, or ion thereof. In some embodiments, D is a generation 4 PAMAM dendrimer, and wherein the radionuclide is 18 F, or ion thereof. In some embodiments, D is a generation 6 PAMAM dendrimer, and wherein the radionuclide is 64 Cu, 90 Y, or 111 In, or ion thereof.
  • R 1 is a radionuclide selected from the group consisting of 18 F, 47 Sc, 51 Cr, 51 Mn, 52 Fe, 60 Cu, 62 Cu, 64 Cu, 67 Cu, 67 Ga, 68 Ga, 72 As, 76 Br, 77 Br, 88 Y, 89 Zr, 90 Y, 94m Tc, 99m Tc, 97 Ru, 103 Ru, 105 Rh, 109 Pd, 110 In, 111 In , 117m Sn, 123 I, 124 I, 125 I, 131 I, 140 La, 141 Ce, 149 Pm, 153 Sm, 161 Tb, 165 Dy, 166 Dy, 166 Ho, 167 Tm, 168 Yb, 175 Yb, 177 Lu, 186 Re, 188 Re, 198 Au, 199 Au, 203 Pb, 211 Bi, 212 Bi, 213 Bi, 214 Bi, and 225 Ac, or
  • the radionuclide is 18 F, 64 Cu, 89 Zr, 90 Y, 111 In, 177 Lu, 203 Pb, or 225 Ac, or ion thereof.
  • the R 1 is 18 F, 44 Sc, 47 Sc, 51 Cr, 51 Mn, 52 Fe, 55 Co, 60 Cu, 61 Cu, 62 Cu, 64 Cu, 67 Cu, 67 Ga, 68 Ga, 72 As, 76 Br, 77 Br, 82 Rb, 86 Y, 88 Y, 89 Sr, 89 Zr, 90 Y, 94m Tc, 99m Tc, 97 Ru, 103 Ru, 105 Rh, 109 Pd, 110 In, 111 In , 117m Sn, 123 I, 124 I, 125 I, 131 I, 133 Xe, 140 La, 141 Ce, 149 Pm, 149 Tb, 152 Tb, 153 Sm, 161 Tb, 165 Dy, 166 Dy, 166 Ho
  • R 1 is 18 F, 64 Cu, 90 Y, 111 In, 177 Lu, or 225 Ac, or ion thereof. In some embodiments, R 1 is 18 F, 64 Cu, or 177 Lu, or ion thereof. In some embodiments, R 1 is 11 C, 13 N, 18 F, 44 Sc, 51 Cr, 35/156 13813260 55 Co, 61 Cu, 64 Cu, 67 Ga, 67 Cu, 68 Ga, 82 Rb, 86 Y, 89 Zr, 89 Sr, 90 Y, ⁇ 99m ⁇ Tc, 111 In, ⁇ 117m ⁇ Sn, 123 I, 124 I, 125 I, 131 I, 133 Xe, 149 Tb, 152 Tb, 153 Sm, 161 Tb, 166 Ho, 166 Ho, 177 Lu, 186 Re, 188 Re, 201 Tl, 203 Pb, 212 Pb, 212 Bi, 213 Bi, 223 Ra, 225 Ac, or 227 Th
  • the radionuclide is 64 Cu, 90 Y, or 111 In, or ion thereof.
  • R 1 is 18 F, 89 Zr, 90 Y, or 177 Lu, or ion thereof.
  • R 1 is 18 F, 64 Cu, 90 Y, or 111 In, or ion thereof.
  • R 1 is 64 Cu, 90 Y, or 111 In, or ion thereof.
  • R 1 is 64 Cu, or ion thereof.
  • R 1 is 90 Y, or ion thereof.
  • R 1 is 111 In, or ion thereof.
  • R 1 is 18 F, or ion thereof.
  • R 1 is a chelator of a radionuclide (i.e., it chelates a radionuclide, but the radionuclide is not present (e.g., DOTA without an ion)).
  • R 1 is a chelator comprising a radionuclide.
  • the chelator may be bound to the radionuclide or unbound to the radionuclide.
  • the chelator is an acyclic chelator, a cyclic chelator, a cryptand, a crown ether, a porphyrin, or a cyclic or acyclic polyphosphonate.
  • the chelator is consisting of linear chelators, macrocyclic chelators, terpyridine chelators, N 3 S chelators, N 2 S 2 chelators, and N 4 chelators.
  • R 1 is DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10- tetraacetic acid), DOTMA (1R,4R,7R,10R)- ⁇ , ⁇ ′, ⁇ ′′, ⁇ ′′′-tetramethyl-1,4,7,10- tetraazacyclododecane-1,4,7,10-tetraacetic acid, DOTAM (1,4,7,10- tetrakis(carbamoylmethyl)-1,4,7,10-tetraazacyclododecane), DOTPA (1,4,7,10- tetraazacyclododecane-1,4,7,10-tetra propionic acid), DO3AM-acetic acid (2
  • the chelator is 2,2′,2′′,2′′′-(1,4,7,10-tetraazacyclododecane-1,4,7,10- tetrayl)tetraacetic acid (DOTA), p-SCN-Bn-Deferoxamine (DFO), hydrazinonicotinamide (HYNIC), diethylenetriaminepentaacetic acid (DTPA), ethylenediaminetetraacetic acid (EDTA), 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid (DO3A), 1,4,8,11- tetraazacyclotetradecane-1,4,8,11-tetraacetic acid (TETA), 1,4,7-triazacyclononane-1,4,7- triacetic acid (NOTA), bisamino bisthiol (BAT), mercapto-acetyl-acetyl-glycyl-glycine (MAG3), monoamidemonoamine
  • DFA
  • the chelator is 2,2′,2′′,2′′′-(1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetrayl)tetraacetic acid (DOTA), 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA), fluorobenzaldehyde, ethylenediaminetetramethylenephosphonic acid (EDTMP), or tetraazacyclododecanetetramethylenephosphonic acid (DOTMP).
  • the chelator is DOTA.
  • R 1 is DOTA chelated to 111 In.
  • R 1 is DOTA chelated to 111 In 3+ .
  • R 1 is DOTA chelated to 177 Lu. In some embodiments, R 1 is DOTA chelated to 177 Lu 3+ . In some embodiments, R 1 is DOTA chelated to 90 Y. In some embodiments, R 1 is DOTA chelated to 90 Y 3+ . In some embodiments, the chelator is NOTA. In some embodiments, R 1 is NOTA chelated to 64 Cu. In some embodiments, R 1 is NOTA chelated to 64 Cu 2+ . In some embodiments, R 1 is NOTA chelated to 177 Lu. In some embodiments, R 1 is NOTA chelated to 177 Lu 3+ . In some embodiments, R 1 is NOTA chelated to 177 Lu 2+ .
  • R 1 is NOTA chelated to 111 In. In some embodiments, R 1 is NOTA chelated to 111 In 3+ . In some embodiments, R 1 is NOTA chelated to 90 Y. In some embodiments, R 1 is NOTA chelated to 90 Y 3+ . In some embodiments, the chelator is NODAGA. In some embodiments, R 1 is NODAGA chelated to 177 Lu. In some embodiments, R 1 is NODAGA chelated to 177 Lu 3+ . In some embodiments, R 1 is NODAGA chelated to 177 Lu 2+ . In some embodiments, R 1 is NODAGA chelated to 64 Cu.
  • R 1 is NODAGA chelated to 64 Cu 2+ . In some embodiments, R 1 is NODAGA chelated to 111 In. In some embodiments, R 1 is NODAGA chelated to 111 In 3+ . In 37/156 13813260 some embodiments, R 1 is NODAGA chelated to 90 Y. In some embodiments, R 1 is NODAGA chelated to 90 Y 3+ . In some embodiments, the chelator is MACROPA. In some embodiments, R 1 is MACROPA chelated to 177 Lu. In some embodiments, R 1 is MACROPA chelated to 177 Lu 3+ . In some embodiments, R 1 is MACROPA chelated to 177 Lu 2+ .
  • R 1 is MACROPA chelated to 64 Cu. In some embodiments, R 1 is MACROPA chelated to 64 Cu 2+ . In some embodiments, R 1 is MACROPA chelated to 111 In. In some embodiments, R 1 is MACROPA chelated to 111 In 3+ . In some embodiments, R 1 is MACROPA chelated to 90 Y. In some embodiments, R 1 is MACROPA chelated to 90 Y 3+ . In some embodiments, R 1 is MACROPA chelated to 225 Ac. In some embodiments, R 1 is MACROPA chelated to 225 Ac 3+ . In some embodiments, the chelator is MACROPA.
  • R 1 is NOTA, DOTA, PEPA, CB-TE2A, NODAGA, DOTAM, MACROPA, SarAr, NODASA, DOTPA, HEHA, NOTP, DOTAGA, TETA, NETA, PCTA-Bn, TETPA, MANOTA, DOTP/DOTMP, or a porphyrin.
  • the chelator is NOTA, DOTA, PEPA, CB-TE2A, NODAGA, DOTAM, MACROPA, SarAr, NODASA, DOTPA, HEHA, NOTP, DOTAGA, TETA, NETA, PCTA-Bn, TETPA, MANOTA, DOTP/DOTMP, or a porphyrin.
  • the chelator and/or R 1 is as in Figure 29B.
  • R 1 is 38/156 13813260 39/156 13813260 some embodiments, certain embodiments, R 1 is .
  • Z is substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, or substituted or unsubstituted heteroalkylene, or 40/156 13813260 substituted or unsubstituted heteroalkenylene.
  • Z is substituted or unsubstituted alkylene.
  • Z is substituted or unsubstituted C1-C6 alkylene.
  • Z is substituted or unsubstituted propylene. In some embodiments, Z .
  • q is an integer from 0-50, inclusive. In some embodiments, q is an integer from 0-20, inclusive. In certain embodiments, q is an integer from 1-20, inclusive. In some embodiments, q is an integer from 0-10, inclusive. In certain embodiments, q is an integer from 1-10, inclusive. In some embodiments, q is 1. In certain embodiments, q is 0.
  • m is an integer from 16-4095, inclusive. In certain embodiments, m is an integer from 52-56, inclusive.
  • n is an integer from 1-20. In some embodiments of Formula (I′) or (I), n is an integer from 1-12, inclusive. In certain embodiments, n is an integer from 1-9, inclusive. In certain embodiments, n is 8, 9, or 10. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5. In some embodiments, n is 6. In some embodiments, n is 7. In some embodiments, n is 8. In some embodiments, n is 9. In some embodiments, n is 10. In some embodiments, n is 11.
  • n is 12. [00101] in some embodiments of Formula (I′) or (I), p is an integer from 0-20, inclusive. In some embodiments, p is an integer from 0-6, inclusive. In some embodiments, p is an integer from 0-3, inclusive. In some embodiments, p is 0, 1, 2, or 3. In some embodiments, p is 0, 1, or 2. In some embodiments, p is 0. In certain embodiments, p is 1. In some embodiments, p is 2. In certain embodiments, p is 3. In certain embodiments, p is 4. In certain embodiments, p is 5. In certain embodiments, p is 6. In certain embodiments, p is 7. In some embodiments, p is 8. In certain embodiments, p is 9.
  • p is 10. In certain embodiments, p is 11. In some embodiments, p is 12. [00102] In some embodiments, p + n is an integer from 1-40, inclusive. In some embodiments, p + n is an integer from 2-30, inclusive. In some embodiments, p + n is an integer from 3-20, inclusive. In some embodiments, p + n is an integer from 3-16, inclusive. In some embodiments, p + n is an integer from 8-16, inclusive. In some embodiments, p + n is an integer from 8-12, inclusive. In some embodiments, p + n is 3. In some embodiments, p + n is 4. In some embodiments, p + n is 5.
  • p + n is 6. In some embodiments, p + n is 7. In some embodiments, p + n is 8. In some embodiments, p + n is 9. In some 41/156 13813260 embodiments, p + n is 10. In some embodiments, p + n is 11. In some embodiments, p + n is 12. In some embodiments, p + n is 13. In some embodiments, p + n is 14. In some embodiments, p + n is 15. In some embodiments, p + n is 16. [00103] In some embodiments, the sum of m, p, and n is 64. In some embodiments, the sum of m, p, and n is 128.
  • the sum of m, p, and n is 256.
  • the dendrimer conjugate of Formula (I′) or (I) is of the formula: , or a pharmaceutically acceptable salt thereof.
  • the dendrimer conjugate of Formula (I′) or (I) is of the formula: , or a pharmaceutically acceptable salt thereof.
  • the dendrimer conjugate of Formula (I′) or (I) is of the formula: , or a pharmaceutically acceptable salt thereof.
  • the dendrimer conjugate of Formula (I′) or (I) is of the formula: , or a pharmaceutically acceptable salt thereof, and D is a generation 4 PAMAM dendrimer.
  • the dendrimer conjugate of Formula (I′) or (I) is of the formula: 42/156 13813260 , or a pharmaceutically acceptable salt thereof.
  • the dendrimer conjugate of Formula (I′) or (I) is of the formula: , or a pharmaceutically acceptable salt thereof, and D is a generation 4 PAMAM dendrimer.
  • the dendrimer conjugate of Formula (I′) or (I) is of the formula: , or a pharmaceutically acceptable salt thereof, wherein n is an integer from 1-9, inclusive. In some embodiments, the dendrimer conjugate of Formula (I′) or (I) is of the formula: , or a pharmaceutically acceptable salt thereof, wherein n is an integer from 1-9, inclusive, and D is a generation 4 PAMAM dendrimer. [00109] In some embodiments, the dendrimer conjugate of Formula (I′) or (I) is of the formula: , or a pharmaceutically acceptable salt thereof.
  • the dendrimer conjugate of Formula (I′) or (I) is of the formula: 43/156 13813260 , or a pharmaceutically acceptable salt thereof, wherein D is a generation 4 PAMAM dendrimer.
  • the dendrimer conjugate of Formula (I′) or (I) is in the form of a dendrimer conjugate, or a pharmaceutically acceptable salt, regioisomer, stereoisomer, or tautomer thereof.
  • the dendrimer conjugate of Formula (I′) or (I) is in the form of a dendrimer conjugate, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.
  • the dendrimer conjugate of Formula (I′) or (I) is in the form of a dendrimer conjugate, or a pharmaceutically acceptable salt, regioisomer, stereoisomer, or tautomer thereof. In some embodiments, the dendrimer conjugate of Formula (I′) or (I) is in the form of a dendrimer conjugate, or a pharmaceutically acceptable salt or tautomer thereof. In some embodiments, the dendrimer conjugate of Formula (I′) or (I) is in the form of a dendrimer conjugate, or a pharmaceutically acceptable salt thereof.
  • the dendrimer conjugate of Formula (I′) or (I) is in the form of a dendrimer conjugate.
  • Dendrimer Conjugates of Formulae (II′) and (II) [00111]
  • D is a dendrimer
  • R 1 is a radionuclide or a chelator of a radionuclide
  • R A is a reactive moiety comprising a cyclic alkene or cyclic alkyne
  • R B is a polycyclic moiety
  • L 1 and L 2 are each independently a linker
  • m is an integer from 16-4095, inclusive
  • n is an integer from 1-20, inclusive
  • p is an integer from 0-20, inclusive.
  • the compound of Formula (II′) is of Formula (II) (e.g., the chelator is chelating a radionuclide).
  • the compound of Formula 44/156 13813260 (II′) that does not comprise a radionuclide being chelated by the chelator is converted to a compound of Formula (II) by introduction of a radionuclide, thus resulting in chelation.
  • dendrimer conjugates of Formula (II): or a pharmaceutically acceptable salt thereof wherein: D is a dendrimer; R 1 is a radionuclide or a chelator comprising a radionuclide; R A is a reactive moiety comprising a cyclic alkene or cyclic alkyne; R B is a polycyclic moiety; L 1 and L 2 are each independently a linker; m is an integer from 16-4095, inclusive; n is an integer from 1-20, inclusive; and p is an integer from 0-20, inclusive.
  • dendrimer conjugate refers to a dendrimer that comprises at least one agent, such as an active agent, imaging agent, or therapeutic agent described herein.
  • the dendrimer is conjugated to the at least one agent through a covalent or non- covalent linkage.
  • the dendrimer is conjugated to a chelator, which can chelate a radionuclide (i.e., an imaging agent).
  • the dendrimer is conjugated to the at least one agent through a chelator, such as a dendrimer conjugate of Formula (II), where R 1 is a chelator comprising a radionuclide.
  • a dendrimer refers to a compound having a molecular architecture with an interior core and layers (or “generations”) of repeating units which are attached to and extend from this interior core, each layer having one or more branching points, and the outermost generation having terminal functional groups.
  • terminal functional groups of a dendrimer include one or more hydroxyl groups, one or more amine groups, and/or one or more carboxyl groups.
  • the terminal functional groups of a dendrimer provide attachment sites through which the at least one agent is conjugated to form the dendrimer conjugate.
  • the at least one agent is conjugated to the dendrimer through an ether bond, an amide bond, or an ester bond formed by conjugation to a terminal functional group of the dendrimer. In some embodiments, the at least one agent is conjugated to the 45/156 13813260 dendrimer through an ether bond or an amide bond. In some embodiments, the at least one agent is conjugated to the dendrimer through an ether bond. [00115] D is a dendrimer as described herein.
  • D is a polyamidoamine (PAMAM), polypropylamine (POPAM), polyethylenimine, polylysine, polyester, iptycene, aliphatic poly(ether), or an aromatic polyether dendrimer.
  • D is a polyamidoamine (PAMAM) dendrimer.
  • D is a polypropylamine (POPAM) dendrimer.
  • D is a polyethylenimine dendrimer.
  • D is a polylysine dendrimer.
  • D is a polyester dendrimer.
  • D is an iptycene dendrimer. In some embodiments, D is an aliphatic poly(ether) dendrimer. In some embodiments, D is an aromatic polyether dendrimer. [00116] In some embodiments of Formula (II′) or (II), D is a generation 4, generation 5, generation 6, generation 7, or generation 8 dendrimer. In some embodiments, D is a generation 4 dendrimer. In some embodiments, D is a generation 5 dendrimer. In some embodiments, D is a generation 6 dendrimer. In some embodiments, D is a generation 7 dendrimer. In some embodiments, D is a generation 8 dendrimer.
  • D is a generation 4, generation 5, generation 6, generation 7, or generation 8 PAMAM dendrimer.
  • D is a generation 4 PAMAM dendrimer.
  • D is a generation 5 PAMAM dendrimer.
  • D is a generation 6 PAMAM dendrimer.
  • D is a generation 7 PAMAM dendrimer.
  • D is a generation 8 PAMAM dendrimer.
  • D is a generation 2, 3, 4, 5, 6, 7, 8, 9, or 10 PAMAM dendrimer, which has 16, 32, 64, 128, 256, 512, 1024, 2048, or 4096 terminal sites, respectively. Accordingly, in some embodiments, D is a generation 2, 3, 4, 5, 6, 7, 8, 9, or 10 PAMAM dendrimer, and m + n + p is 16, 32, 64, 128, 256, 512, 1024, 2048, or 4096, respectively. In some embodiments, D is a generation 4 PAMAM dendrimer, and m + n + p is 64. In some embodiments, D is a generation 5 PAMAM dendrimer, and m + n + p is 128.
  • R 1 is a radionuclide or a chelator of a radionuclide. In some embodiments, R 1 is a radionuclide. In some embodiments, R 1 is a chelator of a radionuclide (i.e., a chelator such as DOTA without the radionuclide present, but will chelate the radionuclide). 46/156 13813260 [00120] In some embodiments of Formula (II), R 1 is a radionuclide or a chelator comprising a radionuclide.
  • R 1 is a radionuclide. In some embodiments, R 1 is a chelator comprising a radionuclide. [00121] In some embodiments of Formula (II′) or (II), the radionuclide is selected from the group consisting of 18 F, 47 Sc, 51 Cr, 51 Mn, 52 Fe, 60 Cu, 62 Cu, 64 Cu, 67 Cu, 67 Ga, 68 Ga, 72 As, 76 Br, 77 Br, 88 Y, 89 Zr, 90 Y, 94m Tc, 99m Tc, 97 Ru, 103 Ru, 105 Rh, 109 Pd, 110 In, 111 In , 117m Sn, 123 I, 124 I, 125 I, embodiments, the radionuclide is 18 F, 64 Cu, 90 Y, or 111 In, or ion thereof.
  • the radionuclide is 18 F, 64 Cu, 89 Zr, 90 Y, 111 In, 177 Lu, 203 Pb, or 225 Ac, or ion thereof. In some embodiments, the radionuclide is 18 F, 64 Cu, 90 Y, 111 In, 177 Lu, or 225 Ac, or ion thereof. In some embodiments, the radionuclide is 18 F, 64 Cu, or 177 Lu, or ion thereof.
  • the radionuclide is 11 C, 13 N, 18 F, 44 Sc, 51 Cr, 55 Co, 61 Cu, 64 Cu, 67 Ga, 67 Cu, 68 Ga, 82 Rb, 86 Y, 89 Zr, 89 Sr, 90 Y, ⁇ 99m ⁇ Tc, 111 In, ⁇ 117m ⁇ Sn, 123 I, 124 I, 125 I, 131 I, 133 Xe, 149 Tb, 152 Tb, 153 Sm, 161 Tb, 166 Ho, 166 Ho, 177 Lu, 186 Re, 188 Re, 201 Tl, 203 Pb, 212 Pb, 212 Bi, 213 Bi, 223 Ra, 225 Ac, or 227 Th, or ion thereof.
  • the radionuclide is 64 Cu, 90 Y, or 111 In, or ion thereof. In some embodiments, the radionuclide is 64 Cu, or ion thereof. In some embodiments, the radionuclide is 90 Y, or ion thereof. In some embodiments, the radionuclide is 111 In, or ion thereof. In some embodiments, the radionuclide is 18 F, or ion thereof. In some embodiments, the radionuclide is 89 Zr, or ion thereof. In some embodiments, the radionuclide is 90 Y, or ion thereof. In some embodiments, the radionuclide is 111 In, or ion thereof.
  • the radionuclide is 177 Lu, or ion thereof. In some embodiments, the radionuclide is 203 Pb, or ion thereof. In some embodiments, the radionuclide is 225 Ac, or ion thereof. In some embodiments, D is a generation 4 PAMAM dendrimer, and wherein the radionuclide is 18 F, or ion thereof. In some embodiments, D is a generation 6 PAMAM dendrimer, and wherein the radionuclide is 64 Cu, 90 Y, or 111 In, or ion thereof.
  • R 1 is a radionuclide selected from the group consisting of 18 F, 47 Sc, 51 Cr, 51 Mn, 52 Fe, 60 Cu, 62 Cu, 64 Cu, 67 Cu, 67 Ga, 68 Ga, 72 As, 76 Br, 77 Br, 88 Y, 89 Zr, 90 Y, 94m Tc, 99m Tc, 97 Ru, 103 Ru, 105 Rh, 109 Pd, 110 In, 111 In , 117m Sn, 123 I, 124 I, 125 I, 47/156 13813260 131 I, 140 La, 141 Ce, 149 Pm, 153 Sm, 161 Tb, 165 Dy, 166 Dy, 166 Ho, 167 Tm, 168 Yb, 175 Yb, 177 Lu, 186 Re, 188 Re, 198 Au, 199 Au, 203 Pb, 211 Bi, 212 Bi, 213 Bi, 214
  • the radionuclide is 18 F, 64 Cu, 89 Zr, 90 Y, 111 In, 177 Lu, 203 Pb, or 225 Ac, or ion thereof.
  • the R 1 is 18 F, 44 Sc, 47 Sc, 51 Cr, 51 Mn, 52 Fe, 55 Co, 60 Cu, 61 Cu, 62 Cu, 64 Cu, 67 Cu, 67 Ga, 68 Ga, 72 As, 76 Br, 77 Br, 82 Rb, 86 Y, 88 Y, 89 Sr, 89 Zr, 90 Y, 94m Tc, 99m Tc, 97 Ru, 103 Ru, 105 Rh, 109 Pd, 110 In, 111 In , 117m Sn, 123 I, 124 I, 125 I, 131 I, 133 Xe, 140 La, 141 Ce, 149 Pm, 149 Tb, 1 88 Re, 198 Au, 199 Au, ion thereof.
  • R 1 is 18 F, 64 Cu, 90 Y, 111 In, 177 Lu, or 225 Ac, or ion thereof. In some embodiments, embodiments, R 1 is 18 F, 64 Cu, or 177 Lu, or ion thereof.
  • R 1 is 11 C, 13 N, 18 F, 44 Sc, 51 Cr, 55 Co, 61 Cu, 64 Cu, 67 Ga, 67 Cu, 68 Ga, 82 Rb, 86 Y, 89 Zr, 89 Sr, 90 Y, ⁇ 99m ⁇ Tc, 111 In, ⁇ 117m ⁇ Sn, 123 I, 124 I, 125 I, 131 I, 133 Xe, 149 Tb, 152 Tb, 153 Sm, 161 Tb, 166 Ho, 166 Ho, 177 Lu, 186 Re, 188 Re, 201 Tl, 203 Pb, 212 Pb, 212 Bi, 213 Bi, 223 Ra, 225 Ac, or 227 Th, or ion thereof.
  • the radionuclide is 64 Cu, 90 Y, or 111 In, or ion thereof.
  • R 1 is 18 F, 89 Zr, 90 Y, or 177 Lu, or ion thereof.
  • R 1 is 18 F, 64 Cu, 90 Y, or 111 In, or ion thereof.
  • R 1 is 64 Cu, 90 Y, or 111 In, or ion thereof.
  • R 1 is 64 Cu, or ion thereof.
  • R 1 is 90 Y, or ion thereof.
  • R 1 is 111 In, or ion thereof.
  • R 1 is 18 F, or ion thereof.
  • R 1 is a chelator of a radionuclide (i.e., it chelates a radionuclide, but the radionuclide is not present (e.g., DOTA without an ion)).
  • R 1 is a chelator comprising a radionuclide.
  • the chelator may be bound to the radionuclide, or unbound to the radionuclide.
  • the chelator is an acyclic chelator, a cyclic chelator, a cryptand, a crown ether, a porphyrin, or a cyclic or acyclic polyphosphonate.
  • the chelator is consisting of linear chelators, macrocyclic chelators, terpyridine chelators, N3S chelators, N2S2 chelators, and N4 chelators.
  • R 1 is DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10- tetraacetic acid), DOTMA (1R,4R,7R,10R)- ⁇ , ⁇ ′, ⁇ ′′, ⁇ ′′′-tetramethyl-1,4,7,10- tetraazacyclododecane-1,4,7,10-tetraacetic acid, DOTAM (1,4,7,10- tetrakis(carbamoylmethyl)-1,4,7,10-tetraazacyclododecane), DOTPA (1,4,7,10- tetraazacyclododecane-1,4,7,10-tetra propionic acid), DO3AM-acetic acid (2
  • the chelator is 2,2′,2′′,2′′′-(1,4,7,10-tetraazacyclododecane-1,4,7,10- tetrayl)tetraacetic acid (DOTA), p-SCN-Bn-Deferoxamine (DFO), hydrazinonicotinamide (HYNIC), diethylenetriaminepentaacetic acid (DTPA), ethylenediaminetetraacetic acid (EDTA), 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid (DO3A), 1,4,8,11- tetraazacyclotetradecane-1,4,8,11-tetraacetic acid (TETA), 1,4,7-triazacyclononane-1,4,7- triacetic acid (NOTA), bisamino bisthiol (BAT), mercapto-acetyl-acetyl-glycyl-glycine (MAG3), monoamidemonoamine
  • DFA
  • the chelator is 2,2′,2′′,2′′′-(1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetrayl)tetraacetic acid (DOTA), 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA), fluorobenzaldehyde, ethylenediaminetetramethylenephosphonic acid (EDTMP), or tetraazacyclododecanetetramethylenephosphonic acid (DOTMP).
  • the chelator is DOTA.
  • R 1 is DOTA chelated to 111 In.
  • R 1 is DOTA chelated to 111 In 3+ .
  • R 1 is DOTA chelated to 177 Lu. In some embodiments, R 1 is DOTA chelated to 177 Lu 3+ . In some embodiments, R 1 is DOTA chelated to 90 Y. In some embodiments, R 1 is DOTA chelated to 90 Y 3+ . In some 49/156 13813260 embodiments, the chelator is NOTA. In some embodiments, R 1 is NOTA chelated to 64 Cu. In some embodiments, R 1 is NOTA chelated to 64 Cu 2+ . In some embodiments, R 1 is NOTA chelated to 177 Lu. In some embodiments, R 1 is NOTA chelated to 177 Lu 3+ .
  • R 1 is NOTA chelated to 177 Lu 2+ . In some embodiments, R 1 is NOTA chelated to 111 In. In some embodiments, R 1 is NOTA chelated to 111 In 3+ . In some embodiments, R 1 is NOTA chelated to 90 Y. In some embodiments, R 1 is NOTA chelated to 90 Y 3+ . In some embodiments, the chelator is NODAGA. In some embodiments, R 1 is NODAGA chelated to 177 Lu. In some embodiments, R 1 is NODAGA chelated to 177 Lu 3+ . In some embodiments, R 1 is NODAGA chelated to 177 Lu 2+ .
  • R 1 is NODAGA chelated to 64 Cu. In some embodiments, R 1 is NODAGA chelated to 64 Cu 2+ . In some embodiments, R 1 is NODAGA chelated to 111 In. In some embodiments, R 1 is NODAGA chelated to 111 In 3+ . In some embodiments, R 1 is NODAGA chelated to 90 Y. In some embodiments, R 1 is NODAGA chelated to 90 Y 3+ . In some embodiments, the chelator is MACROPA. In some embodiments, R 1 is MACROPA chelated to 177 Lu. In some embodiments, R 1 is MACROPA chelated to 177 Lu 3+ .
  • R 1 is MACROPA chelated to 177 Lu 2+ . In some embodiments, R 1 is MACROPA chelated to 64 Cu. In some embodiments, R 1 is MACROPA chelated to 64 Cu 2+ . In some embodiments, R 1 is MACROPA chelated to 111 In. In some embodiments, R 1 is MACROPA chelated to 111 In 3+ . In some embodiments, R 1 is MACROPA chelated to 90 Y. In some embodiments, R 1 is MACROPA chelated to 90 Y 3+ . In some embodiments, R 1 is MACROPA chelated to 225 Ac.
  • R 1 is MACROPA chelated to 225 Ac 3+ .
  • the chelator is MACROPA.
  • R 1 is NOTA, DOTA, PEPA, CB-TE2A, NODAGA, DOTAM, MACROPA, SarAr, NODASA, DOTPA, HEHA, NOTP, DOTAGA, TETA, NETA, PCTA-Bn, TETPA, MANOTA, DOTP/DOTMP, or a porphyrin.
  • the chelator is NOTA, DOTA, PEPA, CB-TE2A, NODAGA, DOTAM, MACROPA, SarAr, NODASA, DOTPA, HEHA, NOTP, DOTAGA, TETA, NETA, PCTA-Bn, TETPA, MANOTA, DOTP/DOTMP, or a porphyrin.
  • the chelator and/or R 1 is as in Figure 29B.
  • R 1 is 50/156 13813260 51/156 13813260 [00124]
  • R A is a reactive moiety comprising a cyclic alkene or cyclic alkyne. In some embodiments, R A is cyclooctene.
  • R A is: 52/156 13813260 some embodiments, R A is: .
  • R A is dibenzocyclooctyne.
  • RA is dibenzoazocyne.
  • R B is a polycyclic moiety.
  • R B is a polycyclic moiety resulting from cycloaddition reaction of the cyclic alkene or cyclic alkyne of R A .
  • R B is a polycyclic moiety resulting from cycloaddition reaction of cyclooctene.
  • R B is a polycyclic moiety resulting from cycloaddition reaction of cyclooctene with substituted or unsubstituted tetrazine. In some embodiments, R B is a polycyclic moiety resulting from cycloaddition reaction of dibenzoazocyne. In some embodiments, R B is a polycyclic moiety resulting from cycloaddition reaction of dibenzoazocyne with substituted or unsubstituted azide. In some embodiments, R B is . 53/156 13813260 [00127] As provided herein, L 1 and L 2 are each independently a linker.
  • L 1 and L 2 are each independently a linker selected from substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted alkynylene, substituted or unsubstituted heteroalkenylene, substituted or unsubstituted heteroalkynylene, substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, substituted or unsubstituted acylene, and combinations thereof.
  • L 1 is a linker selected from substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted alkynylene, substituted or unsubstituted heteroalkenylene, substituted or unsubstituted heteroalkynylene, substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, substituted or unsubstituted acylene, and combinations thereof.
  • L 2 is a linker selected from substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted alkynylene, substituted or unsubstituted heteroalkenylene, substituted or unsubstituted heteroalkynylene, substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, substituted or unsubstituted acylene, and combinations thereof.
  • L 2 is substituted or unsubstituted alkylene wherein one or more backbone carbon atoms have been replaced with one or more groups independently selected from (-CH 2 -O-CH 2 -) and -NH-. In certain embodiments, L 2 is substituted or unsubstituted alkylene wherein one or more backbone carbon atoms have been replaced with one or more groups independently selected from -arylene- and -O-. In certain embodiments, L 2 is substituted or unsubstituted alkylene wherein one or more backbone carbon atoms have been replaced with one or more groups independently selected from - 55/156 13813260 arylene- and -NH-. In some embodiments, L 2 is .
  • L 2 is .
  • m is an integer from 16-4095, inclusive. In certain embodiments, m is an integer from 200-300, inclusive. In certain embodiments, m is an integer from 240-255, inclusive. In some embodiments, m is 251. In certain embodiments, m is an integer from 50-70, inclusive. In certain embodiments, m is an integer from 54-63, inclusive. In some embodiments, m is 60. [00131] In some embodiments of Formula (II′) or (II), n is an integer from 1-20, inclusive.
  • n is an integer from 1-16, inclusive In some embodiments, n is an integer from 1-12, inclusive. In some embodiments n is an integer from 1-10, inclusive. In some embodiments, n is an integer from 2-6, inclusive. In some embodiments, n is an integer from 3- 7, inclusive. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5. In some embodiments, n is 6. In some embodiments, n is 7. In some embodiments, n is 8. In some embodiments, n is 9. In some embodiments, n is 10. In some embodiments, n is 11. In some embodiments, n is 12.
  • p is an integer from 0-20, inclusive. In some embodiments, p is an integer from 0-6, inclusive. In some embodiments, p is an integer from 0-3, inclusive. In some embodiments, p is 0, 1, 2, or 3. In some embodiments, p is 0, 1, or 2. In some embodiments, p is 0. In certain embodiments, p is 1. In some embodiments, p is 2. In certain embodiments, p is 3. In certain embodiments, p is 4. In certain embodiments, p is 5. In certain embodiments, p is 6. In certain embodiments, p is 7. In some embodiments, p is 8. In certain embodiments, p is 9. In some embodiments, p is 10.
  • p is 11. In some embodiments, p is 12. [00133] In some embodiments, p + n is an integer from 1-40, inclusive. In some embodiments, p + n is an integer from 2-30, inclusive. In some embodiments, p + n is an integer from 3-20, 56/156 13813260 inclusive. In some embodiments, p + n is an integer from 3-16, inclusive. In some embodiments, p + n is an integer from 8-16, inclusive. In some embodiments, p + n is an integer from 8-12, inclusive. In some embodiments, p + n is 3. In some embodiments, p + n is 4. In some embodiments, p + n is 5. In some embodiments, p + n is 6.
  • p + n is 7. In some embodiments, p + n is 8. In some embodiments, p + n is 9. In some embodiments, p + n is 10. In some embodiments, p + n is 11. In some embodiments, p + n is 12. In some embodiments, p + n is 13. In some embodiments, p + n is 14. In some embodiments, p + n is 15. In some embodiments, p + n is 16. [00134] In some embodiments, the sum of m, p, and n is 64. In some embodiments, the sum of m, p, and n is 128. In some embodiments, the sum of m, p, and n is 256.
  • m, n, p, and D are as defined below.
  • m is an integer from 50-70, inclusive; n is an integer from 1-10, inclusive; p is an integer from 0-10, inclusive; and D is a generation 4 PAMAM dendrimer.
  • m is an integer from 50-70, inclusive; n is an integer from 2-6, inclusive; p is an integer from 0-6, inclusive; and D is a generation 4 PAMAM dendrimer.
  • m is an integer from 54-63, inclusive; p is an integer from 0-10, inclusive; n is an integer from 1-10, inclusive; and D is a generation 4 PAMAM dendrimer.
  • m is 60; p is an integer from 0-6, inclusive; n is an integer from 2-6, inclusive; and D is a generation 4 PAMAM dendrimer.
  • m is an integer from 200- 300, inclusive; n is an integer from 3-7, inclusive; p is an integer from 0-7, inclusive; and D is a generation 6 PAMAM dendrimer.
  • m is an integer from 240-255, inclusive; n is an integer from 1-16, inclusive; p is an integer from 0-16, inclusive; and D is a generation 6 PAMAM dendrimer.
  • m is an integer from 240-255, inclusive; n is an integer from 3-7, inclusive; p is an integer from 0-7, inclusive; and D is a generation 6 PAMAM dendrimer.
  • m is 251; p is 5; n is 5; and D is a generation 6 PAMAM dendrimer.
  • m is 251; p is 0; n is 5; and D is a generation 6 PAMAM dendrimer.
  • m is an integer from 50-70, inclusive; n is an integer from 1- 10, inclusive; p is an integer from 0-5, inclusive; and D is a generation 4 PAMAM dendrimer.
  • m is an integer from 50-70, inclusive; n is an integer from 2-6, inclusive; p is an integer from 0-5, inclusive; and D is a generation 4 PAMAM dendrimer.
  • m is an integer from 54-63, inclusive; p is an integer from 0-5, inclusive; n is an integer from 1-10, inclusive; and D is a generation 4 PAMAM dendrimer.
  • m is 60; p is an integer from 0-5, inclusive; n is an integer from 2-6, inclusive; 57/156 13813260 and D is a generation 4 PAMAM dendrimer. In some embodiments, m is an integer from 200- 300, inclusive; n is an integer from 3-7, inclusive; p is an integer from 0-5, inclusive; and D is a generation 6 PAMAM dendrimer. In certain embodiments, m is an integer from 240-255, inclusive; n is an integer from 1-16, inclusive; p is an integer from 0-5, inclusive; and D is a generation 6 PAMAM dendrimer.
  • m is an integer from 240-255, inclusive; n is an integer from 3-7, inclusive; p is an integer from 0-5, inclusive; and D is a generation 6 PAMAM dendrimer.
  • m is an integer from 50-70, inclusive; n is an integer from 1- 10, inclusive; p is an integer from 0-3, inclusive; and D is a generation 4 PAMAM dendrimer.
  • m is an integer from 50-70, inclusive; n is an integer from 2-6, inclusive; p is an integer from 0-3, inclusive; and D is a generation 4 PAMAM dendrimer.
  • m is an integer from 54-63, inclusive; p is an integer from 0-3, inclusive; n is an integer from 1-10, inclusive; and D is a generation 4 PAMAM dendrimer.
  • m is 60; p is an integer from 0-3, inclusive; n is an integer from 2-6, inclusive; and D is a generation 4 PAMAM dendrimer.
  • m is an integer from 200- 300, inclusive; n is an integer from 3-7, inclusive; p is an integer from 0-3, inclusive; and D is a generation 6 PAMAM dendrimer.
  • m is an integer from 240-255, inclusive; n is an integer from 1-16, inclusive; p is an integer from 0-3, inclusive; and D is a generation 6 PAMAM dendrimer.
  • m is an integer from 240-255, inclusive; n is an integer from 3-7, inclusive; p is an integer from 0-3, inclusive; and D is a generation 6 PAMAM dendrimer.
  • the dendrimer conjugate of Formula (II′) or (II) is of the formula: , or a pharmaceutically acceptable salt thereof.
  • the dendrimer conjugate of Formula (II′) or (II) is of the formula: 58/156 13813260 , or a pharmaceutically acceptable salt thereof.
  • the dendrimer conjugate of Formula (II′) or (II) is of the formula: , or a pharmaceutically acceptable salt thereof.
  • the dendrimer conjugate of Formula (II′) or (II) is of the formula: , or a pharmaceutically acceptable salt thereof.
  • the dendrimer conjugate of Formula (II′) or (II) is of the formula: , or a pharmaceutically acceptable salt thereof.
  • the dendrimer conjugate of Formula (II′) or (II) is of the formula: , or a pharmaceutically acceptable salt thereof.
  • the dendrimer conjugate of Formula (II′) or (II) is of the formula: , or a pharmaceutically acceptable salt thereof.
  • the dendrimer conjugate of Formula (II′) or (II) is of the formula: , or a pharmaceutically acceptable salt thereof.
  • the dendrimer conjugate of Formula (II′) or (II) is of the formula: , or a pharmaceutically acceptable salt thereof.
  • the dendrimer conjugate of Formula (II′) or (II) is of the formula: 60/156 13813260 , or a pharmaceutically acceptable salt thereof.
  • the dendrimer conjugate of Formula (II′) or (II) is of the formula: , or a pharmaceutically acceptable salt thereof.
  • the dendrimer conjugate of Formula (II′) or (II) is of the formula: dendrimer conjugate is of the formula: , or a pharmaceutically acceptable salt thereof.
  • the dendrimer conjugate of Formula (II′) is of the formula: , or a pharmaceutically acceptable salt thereof.
  • the dendrimer conjugate of Formula (II′) is of the formula: 61/156 13813260 , or a pharmaceutically acceptable salt thereof. [00152] In some embodiments, the dendrimer conjugate of Formula (II′) is of the formula: , or a pharmaceutically acceptable salt thereof. [00153] In some embodiments, the dendrimer conjugate of Formula (II′) is of the formula: , or a pharmaceutically acceptable salt thereof. [00154] In some embodiments, the dendrimer conjugate of Formula (II′) is of the formula: , or a pharmaceutically acceptable salt thereof.
  • the dendrimer conjugate of Formula (II′) is of the formula: 62/156 13813260 , or a pharmaceutically acceptable salt thereof. [00156] In some embodiments, the dendrimer conjugate of Formula (II′) is of the formula: , or a pharmaceutically acceptable salt thereof. [00157] In some embodiments, the dendrimer conjugate of Formula (II′) is of the formula: , or a pharmaceutically acceptable salt thereof. [00158] In some embodiments, the dendrimer conjugate of Formula (II′) is of the formula: , or a pharmaceutically acceptable salt thereof.
  • the dendrimer conjugate of Formula (II′) is of the formula: 63/156 13813260 , or a pharmaceutically acceptable salt thereof. [00160] In some embodiments, the dendrimer conjugate of Formula (II′) is of the formula: , or a pharmaceutically acceptable salt thereof. [00161] In some embodiments, the dendrimer conjugate of Formula (II′) is of the formula: , or a pharmaceutically acceptable salt thereof. [00162] In some embodiments, the dendrimer conjugate of Formula (II′) is of the formula: , or a pharmaceutically acceptable salt thereof.
  • the dendrimer conjugate of Formula (II′) is of the formula: 64/156 13813260 , or a pharmaceutically acceptable salt thereof. [00164] In some embodiments, the dendrimer conjugate of Formula (II′) is of the formula: , or a pharmaceutically acceptable salt thereof. [00165] In some embodiments, the dendrimer conjugate of Formula (II′) is of the formula: , or a pharmaceutically acceptable salt thereof. [00166] In some embodiments, the dendrimer conjugate of Formula (II′) is of the formula: , or a pharmaceutically acceptable salt thereof.
  • the dendrimer conjugate of Formula (II′) is of the formula: 65/156 13813260 , or a pharmaceutically acceptable salt thereof. [00168] In some embodiments, the dendrimer conjugate of Formula (II′) is of the formula: , or a pharmaceutically acceptable salt thereof. [00169] In some embodiments, the dendrimer conjugate of Formula (II′) is of the formula: , or a pharmaceutically acceptable salt thereof. [00170] In some embodiments, the dendrimer conjugate of Formula (II′) is of the formula: , or a pharmaceutically acceptable salt thereof.
  • the dendrimer conjugate of Formula (II′) is of the formula: 66/156 13813260 , or a pharmaceutically acceptable salt thereof.
  • the dendrimer conjugate of Formula (II′) is of the formula: , or a pharmaceutically acceptable salt thereof.
  • the dendrimer conjugate of Formula (II′) is of the formula: , or a pharmaceutically acceptable salt thereof.
  • the dendrimer conjugate of Formula (II′) is of the formula: , or a pharmaceutically acceptable salt thereof.
  • the dendrimer conjugate of Formula (II′) is of the formula: 67/156 13813260 , or a pharmaceutically acceptable salt thereof.
  • the dendrimer conjugate of Formula (II′) is of the formula: , or a pharmaceutically acceptable salt thereof.
  • the dendrimer conjugate of Formula (II′) is of the formula: , or a pharmaceutically acceptable salt thereof.
  • the dendrimer conjugate of Formula (II′) is of the formula: , or a pharmaceutically acceptable salt thereof.
  • the dendrimer conjugate of Formula (II′) is of the formula: 68/156 13813260
  • the dendrimer conjugate of Formula (II′) is of the formula: , or a pharmaceutically acceptable salt thereof. [00181] In some embodiments, the dendrimer conjugate of Formula (II′) is of the formula: 69/156 13813260
  • the dendrimer conjugate of Formula (II) is of the formula: , or a pharmaceutically acceptable salt thereof.
  • the dendrimer conjugate of Formula (II) is of the formula: , or a pharmaceutically acceptable salt thereof.
  • the dendrimer conjugate of Formula (II) is of the formula: 70/156 13813260 , or a pharmaceutically acceptable salt thereof.
  • the dendrimer conjugate of Formula (II) is of the formula: , or a pharmaceutically acceptable salt thereof.
  • the dendrimer conjugate of Formula (II) is of the formula: , or a pharmaceutically acceptable salt thereof.
  • the dendrimer conjugate of Formula (II) is of the formula: , or a pharmaceutically acceptable salt thereof.
  • the dendrimer conjugate of Formula (II) is of the formula: 71/156 13813260 , or a pharmaceutically acceptable salt thereof.
  • the dendrimer conjugate of Formula (II) is of the formula: , or a pharmaceutically acceptable salt thereof.
  • the dendrimer conjugate of Formula (II) is of the formula: , or a pharmaceutically acceptable salt thereof.
  • the dendrimer conjugate of Formula (II) is of the formula: , or a pharmaceutically acceptable salt thereof.
  • 72/156 13813260 In some embodiments, the dendrimer conjugate of Formula (II) is of the formula: , or a pharmaceutically acceptable salt thereof.
  • the dendrimer conjugate of Formula (II) is of the formula: , or a pharmaceutically acceptable salt thereof.
  • the dendrimer conjugate of Formula (II) is of the formula: , or a pharmaceutically acceptable salt thereof.
  • the dendrimer conjugate of Formula (II) is of the formula: , or a pharmaceutically acceptable salt thereof.
  • the dendrimer conjugate of Formula (II) is of the formula: 73/156 13813260 , or a pharmaceutically acceptable salt thereof.
  • the dendrimer conjugate of Formula (II) is of the formula: , or a pharmaceutically acceptable salt thereof.
  • the dendrimer conjugate of Formula (II) is of the formula: , or a pharmaceutically acceptable salt thereof.
  • the dendrimer conjugate of Formula (II) is of the formula: , or a pharmaceutically acceptable salt thereof.
  • the dendrimer conjugate of Formula (II) is of the formula: 74/156 13813260 , or a pharmaceutically acceptable salt thereof.
  • the dendrimer conjugate of Formula (II) is of the formula: , or a pharmaceutically acceptable salt thereof.
  • the dendrimer conjugate of Formula (II) is of the formula: , or a pharmaceutically acceptable salt thereof.
  • the dendrimer conjugate of Formula (II) is of the formula: , or a pharmaceutically acceptable salt thereof.
  • the dendrimer conjugate of Formula (II) is of the formula: 75/156 13813260 , or a pharmaceutically acceptable salt thereof.
  • the dendrimer conjugate of Formula (II) is of the formula: , or a pharmaceutically acceptable salt thereof.
  • the dendrimer conjugate of Formula (II) is of the formula: , or a pharmaceutically acceptable salt thereof.
  • the dendrimer conjugate of Formula (II) is of the formula: , or a pharmaceutically acceptable salt thereof.
  • the dendrimer conjugate of Formula (II) is of the formula: 76/156 13813260 , or a pharmaceutically acceptable salt thereof.
  • the dendrimer conjugate of Formula (II) is of the formula: , or a pharmaceutically acceptable salt thereof.
  • the dendrimer conjugate of Formula (II) is of the formula: , or a pharmaceutically acceptable salt thereof. [00211] In some embodiments, the dendrimer conjugate of Formula (II) is of the formula: , or a pharmaceutically acceptable salt thereof. [00212] In some embodiments, the dendrimer conjugate of Formula (II) is of the formula: 77/156 13813260 , or a pharmaceutically acceptable salt thereof. [00213] In some embodiments, the dendrimer conjugate of Formula (II) is of the formula: , or a pharmaceutically acceptable salt thereof.
  • the dendrimer conjugate of Formula (II) is of the formula: , or a pharmaceutically acceptable salt thereof.
  • the dendrimer conjugate of Formula (II) is of the formula: , [00216] In some embodiments, the dendrimer conjugate of Formula (II) is of the formula: 78/156 13813260 , or a pharmaceutically acceptable salt thereof. [00217] In some embodiments, the dendrimer conjugate of Formula (II) is of the formula: or a pharmaceutically acceptable salt thereof. [00218] In some embodiments, the dendrimer conjugate of Formula (II) is of the formula: , or a pharmaceutically acceptable salt thereof.
  • the dendrimer conjugate of Formula (II) is of the formula: , or a pharmaceutically acceptable salt thereof.
  • the dendrimer conjugate of Formula (II) is of the formula: 79/156 13813260 , or a pharmaceutically acceptable salt thereof.
  • p is 0.
  • the dendrimer conjugate is of the formula: , or a pharmaceutically acceptable salt thereof.
  • the dendrimer conjugate is of the formula: , or a pharmaceutically acceptable salt thereof.
  • the dendrimer conjugate is of the formula: , or a pharmaceutically acceptable salt thereof.
  • the dendrimer conjugate of Formula (II′) is of the formula: 80/156 13813260 , or a pharmaceutically acceptable salt thereof.
  • the dendrimer conjugate of Formula (II′) is of the formula: , or a pharmaceutically acceptable salt thereof.
  • the dendrimer conjugate of Formula (II′) is of the formula: , or a pharmaceutically acceptable salt thereof.
  • the dendrimer conjugate of Formula (II′) is of the formula: 81/156 13813260 , or a pharmaceutically acceptable salt thereof. [00229] In some embodiments, the dendrimer conjugate of Formula (II′) is of the formula: , or a pharmaceutically acceptable salt thereof. [00230] In some embodiments, the dendrimer conjugate of Formula (II′) is of the formula: , or a pharmaceutically acceptable salt thereof. [00231] In some embodiments, the dendrimer conjugate of Formula (II′) is of the formula: 82/156 13813260
  • the dendrimer conjugate of Formula (II′) is of the formula: , or a pharmaceutically acceptable salt thereof.
  • the dendrimer conjugate of Formula (II′) is of the formula: , or a pharmaceutically acceptable salt thereof.
  • the dendrimer conjugate of Formula (II′) is of the formula: , 83/156 13813260 or a pharmaceutically acceptable salt thereof.
  • the dendrimer conjugate of Formula (II′) is of the formula: , or a pharmaceutically acceptable salt thereof.
  • the dendrimer conjugate of Formula (II′) is of the formula: , or a pharmaceutically acceptable salt thereof. [00237] In some embodiments, the dendrimer conjugate of Formula (II′) is of the formula: , or a pharmaceutically acceptable salt thereof. [00238] In some embodiments, the dendrimer conjugate of Formula (II′) is of the formula: 84/156 13813260 , or a pharmaceutically acceptable salt thereof. [00239] In some embodiments, the dendrimer conjugate of Formula (II′) is of the formula: , or a pharmaceutically acceptable salt thereof.
  • the dendrimer conjugate of Formula (II′) is of the formula: , or a pharmaceutically acceptable salt thereof. [00241] In some embodiments, the dendrimer conjugate of Formula (II′) is of the formula: , or a pharmaceutically acceptable salt thereof. 85/156 13813260 [00242] In some embodiments, the dendrimer conjugate of Formula (II′) is of the formula: , [00243] In some embodiments, the dendrimer conjugate of Formula (II′) is of the formula: , or a pharmaceutically acceptable salt thereof.
  • the dendrimer conjugate of Formula (II′) is of the formula: , or a pharmaceutically acceptable salt thereof.
  • the dendrimer conjugate of Formula (II′) is of the formula: 86/156 13813260 , or a pharmaceutically acceptable salt thereof.
  • the dendrimer conjugate of Formula (II′) is of the formula: , or a pharmaceutically acceptable salt thereof.
  • the dendrimer conjugate of Formula (II′) is of the formula: , or a pharmaceutically acceptable salt thereof.
  • the dendrimer conjugate of Formula (II′) is of the formula: , or a pharmaceutically acceptable salt thereof. 87/156 13813260 [00249] In some embodiments, the dendrimer conjugate of Formula (II′) is of the formula: , or a pharmaceutically acceptable salt thereof. [00250] In some embodiments, the dendrimer conjugate of Formula (II′) is of the formula: , or a pharmaceutically acceptable salt thereof. [00251] In some embodiments, the dendrimer conjugate of Formula (II′) is of the formula: , or a pharmaceutically acceptable salt thereof.
  • the dendrimer conjugate of Formula (II′) is of the formula: 88/156 13813260 , or a pharmaceutically acceptable salt thereof. [00253] In some embodiments, the dendrimer conjugate of Formula (II′) is of the formula: , or a pharmaceutically acceptable salt thereof. [00254] In some embodiments, the dendrimer conjugate of Formula (II′) is of the formula: , or a pharmaceutically acceptable salt thereof. [00255] In some embodiments, the dendrimer conjugate of Formula (II′) is of the formula: 89/156 13813260
  • the dendrimer conjugate of Formula (II′) is of the formula: , or a pharmaceutically acceptable salt thereof.
  • the dendrimer conjugate of Formula (II) is of the formula: 90/156 13813260 , or a pharmaceutically acceptable salt thereof.
  • the dendrimer conjugate of Formula (II) is of the formula: , or a pharmaceutically acceptable salt thereof.
  • the dendrimer conjugate of Formula (II) is of the formula: , or a pharmaceutically acceptable salt thereof.
  • the dendrimer conjugate of Formula (II) is of the formula: 91/156 13813260 , or a pharmaceutically acceptable salt thereof. [00261] In some embodiments, the dendrimer conjugate of Formula (II) is of the formula: , or a pharmaceutically acceptable salt thereof. [00262] In some embodiments, the dendrimer conjugate of Formula (II) is of the formula: , or a pharmaceutically acceptable salt thereof. [00263] In some embodiments, the dendrimer conjugate of Formula (II) is of the formula: 92/156 13813260 , or a pharmaceutically acceptable salt thereof.
  • the dendrimer conjugate of Formula (II) is of the formula: , or a pharmaceutically acceptable salt thereof.
  • the dendrimer conjugate of Formula (II) is of the formula: , or a pharmaceutically acceptable salt thereof.
  • the dendrimer conjugate of Formula (II) is of the formula: 93/156 13813260 , or a pharmaceutically acceptable salt thereof.
  • the dendrimer conjugate of Formula (II) is of the formula: , or a pharmaceutically acceptable salt thereof.
  • the dendrimer conjugate of Formula (II) is of the formula: , or a pharmaceutically acceptable salt thereof.
  • the dendrimer conjugate of Formula (II) is of the formula: 94/156 13813260 , or a pharmaceutically acceptable salt thereof.
  • the dendrimer conjugate of Formula (II) is of the formula: , or a pharmaceutically acceptable salt thereof.
  • the dendrimer conjugate of Formula (II) is of the formula: , or a pharmaceutically acceptable salt thereof.
  • the dendrimer conjugate of Formula (II) is of the formula: 95/156 13813260 , or a pharmaceutically acceptable salt thereof. [00273] In some embodiments, the dendrimer conjugate of Formula (II) is of the formula: , or a pharmaceutically acceptable salt thereof. [00274] In some embodiments, the dendrimer conjugate of Formula (II) is of the formula: , or a pharmaceutically acceptable salt thereof. [00275] In some embodiments, the dendrimer conjugate of Formula (II) is of the formula: , or a pharmaceutically acceptable salt thereof.
  • the dendrimer conjugate of Formula (II) is of the formula: , or a pharmaceutically acceptable salt thereof. [00277] In some embodiments, the dendrimer conjugate of Formula (II) is of the formula: , or a pharmaceutically acceptable salt thereof. [00278] In some embodiments, the dendrimer conjugate of Formula (II) is of the formula: , or a pharmaceutically acceptable salt thereof. [00279] In some embodiments, the dendrimer conjugate of Formula (II) is of the formula: , 97/156 13813260 or a pharmaceutically acceptable salt thereof.
  • the dendrimer conjugate of Formula (II) is of the formula: , or a pharmaceutically acceptable salt thereof.
  • the dendrimer conjugate of Formula (II) is of the formula: , or a pharmaceutically acceptable salt thereof.
  • the dendrimer conjugate of Formula (II) is of the formula: , or a pharmaceutically acceptable salt thereof.
  • the dendrimer conjugate of Formula (II) is of the formula: 98/156 13813260 , or a pharmaceutically acceptable salt thereof.
  • the dendrimer conjugate of Formula (II) is of the formula: , or a pharmaceutically acceptable salt thereof. [00285] In some embodiments, the dendrimer conjugate of Formula (II) is of the formula: , or a pharmaceutically acceptable salt thereof. [00286] In some embodiments, the dendrimer conjugate of Formula (II) is of the formula: 99/156 13813260
  • the dendrimer conjugate of Formula (II) is of the formula: , or a pharmaceutically acceptable salt thereof.
  • the dendrimer conjugate of Formula (II) is of the formula: , or a pharmaceutically acceptable salt thereof.
  • the dendrimer conjugate of Formula (II) is of the formula: 100/156 13813260
  • the dendrimer conjugate of Formula (II) is of the formula: , or a pharmaceutically acceptable salt thereof.
  • the dendrimer conjugate of Formula (II) is of the formula: , or a pharmaceutically acceptable salt thereof.
  • the dendrimer conjugate of Formula (II) is of the formula: 101/156 13813260 , or a pharmaceutically acceptable salt thereof.
  • the dendrimer conjugate of Formula (II) is of the formula: , or a pharmaceutically acceptable salt thereof.
  • the dendrimer conjugate of Formula (II) is of the formula: , or a pharmaceutically acceptable salt thereof. [00295] In some embodiments, the dendrimer conjugate of Formula (II) is of the formula: 102/156 13813260
  • the dendrimer conjugate is of the formula as depicted in any one of FIGs.28A-28H.
  • the dendrimer conjugate of Formula (II′) or (II) is in the form of a dendrimer conjugate, or a pharmaceutically acceptable salt, regioisomer, stereoisomer, or tautomer thereof.
  • the dendrimer conjugate of Formula (II′) or (II) is in the form of a dendrimer conjugate, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.
  • the dendrimer conjugate of Formula (II′) or (II) is in the form of a dendrimer conjugate, or a pharmaceutically acceptable salt, regioisomer, stereoisomer, or tautomer thereof. In some embodiments, the dendrimer conjugate of Formula (II′) or (II) is in the form of a dendrimer conjugate, or a pharmaceutically acceptable salt or tautomer thereof. In some embodiments, the dendrimer conjugate of Formula (II′) or (II) is in the form of a dendrimer conjugate, or a pharmaceutically acceptable salt thereof.
  • the dendrimer conjugate of Formula (II′) or (II) is in the form of a dendrimer conjugate.
  • compositions [00298] Also provided herein are compositions. In one aspect, provided herein are compositions comprising a dendrimer conjugate disclosed herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the composition further comprises a pharmaceutically acceptable excipient.
  • the dendrimer conjugates and compositions provided herein can be administered by any route, including enteral (e.g., oral), parenteral, intravenous, intramuscular, intra-arterial, intramedullary, intrathecal, subcutaneous, intraventricular, transdermal, interdermal, rectal, intravaginal, intraperitoneal, topical (as by powders, ointments, creams, and/or drops), mucosal, nasal, bucal, sublingual; by intratracheal instillation, bronchial instillation, and/or 103/156 13813260 inhalation; and/or as an oral spray, nasal spray, and/or aerosol.
  • enteral e.g., oral
  • parenteral intravenous, intramuscular, intra-arterial, intramedullary
  • intrathecal subcutaneous, intraventricular, transdermal, interdermal, rectal, intravaginal, intraperitoneal
  • topical as by powders, ointments, creams,
  • a composition comprises a dendrimer conjugate disclosed herein and one or more pharmaceutically acceptable excipients.
  • Suitable pharmaceutically acceptable excipients include solvents, diluents, pH modifying agents, preservatives, antioxidants, suspending agents, wetting agents, viscosity modifiers, tonicity agents, stabilizing agents, and combinations thereof.
  • Suitable pharmaceutically acceptable excipients are, in some embodiments, selected from materials which are generally recognized as safe (GRAS) and may be administered to an individual without causing undesirable biological side effects or unwanted interactions.
  • GRAS generally recognized as safe
  • dendrimer conjugates and compositions provided herein are formulated for use in radionuclide imaging and/or radiotherapy.
  • a composition to be administered to a subject has a radioactivity of between about 0.01 mCi and about 100 mCi, between about 1 mCi and about 20 mCi, or between about 1 mCi and about 20 mCi.
  • a composition to be administered to a subject is in a volume of between about 0.01 mL and about 10 mL.
  • a composition to be administered to a subject has a concentration of between about 0.01 mCi per mL and about 100 mCi per mL.
  • the disclosure provides methods of imaging a tissue in a subject.
  • the tissue in the subject is a tissue of the central nervous system.
  • the subject has or is suspected of having a neurological disorder, an autoimmune disorder, or a cancer.
  • the subject has or is suspected of having a neurodegenerative disorder.
  • the neurodegenerative disorder is selected from the group consisting of amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease.
  • the 104/156 13813260 neurodegenerative disorder is multiple sclerosis (MS).
  • the neurodegenerative disorder is relapsing remitting MS, primary progressive MS, or secondary progressive MS.
  • methods of imaging a tissue in a subject comprising: administering the dendrimer conjugate or composition thereof to a subject; and obtaining an image representation of a tissue in the subject.
  • an “image representation” refers to any depiction of the spatial organization or arrangement of one or more objects or events, or any data obtained from an imaging methodology that is representative of or may be used to construct such depiction.
  • an image representation is a two-dimensional depiction.
  • an image representation is a three-dimensional depiction.
  • image representations include, but are not limited to, images, photographs, videos, x-rays, microfiche, microfilm, or any other recordings or depictions of the physical appearance or arrangement of any object or event by any technique.
  • an image representation can be produced from any data containing positional or spatial information.
  • Image representations encompass any digital image or video retrievable from computer storage. [00305]
  • methods of imaging described herein comprise: administering a dendrimer conjugate or composition thereof to a subject; obtaining an image representation of a tissue in the subject; and evaluating the tissue in the subject based on the image representation.
  • the image representation may be used to evaluate the tissue, for example, based on the presence, absence, and/or location of the dendrimer conjugate detected therein.
  • the image representation can be used to diagnose, monitor, and/or evaluate a disease or disorder in a subject.
  • a disease or disorder in a subject can be identified or diagnosed by detecting the dendrimer conjugate in the image representation.
  • a disease or disorder in a subject can be monitored or evaluated by comparing the image representation with one or more previous and/or subsequent image representations.
  • the image representation is one of a series of image representations obtained at different time points.
  • the methods may be used to monitor or evaluate the progression, recurrence, or regression of a disease or disorder in a subject.
  • one or more image representations can be obtained before, during, and/or after a particular therapeutic regimen.
  • the image representation can be used to monitor or evaluate the effects of a particular therapy.
  • methods of imaging described herein comprise: administering a dendrimer conjugate or composition thereof to a subject; obtaining an image representation of a tissue in the subject; and detecting the dendrimer conjugate in the image representation.
  • detection of the dendrimer conjugate in the image representation is indicative of one or more sites of inflammation in the tissue of the subject.
  • the one or more sites of inflammation in the tissue of the subject are associated with an inflammatory or autoimmune disease.
  • the inflammatory or autoimmune disease is selected from the group consisting of arthritis, inflammatory bowel disease, alopecia areata, ankylosing spondylitis, antiphospholipid syndrome, autoimmune Addison’s disease, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune inner ear disease, autoimmune lymphoproliferative syndrome, autoimmune thrombocytopenic purpura, Bechet’s disease, bullous pemphigoid, cardiomyopathy, celiac sprue-dermatitis, chronic fatigue syndrome, chronic inflammatory demyelinating polyneuropathy, cicatricial pemphigoid, cold agglutinin disease, Crest syndrome, Crohn’s disease, Degos disease, dermatomyositis, discoid lupus, essential mixed cryoglobulinemia, fibromyalgia, Graves’ disease, Guillain-Barré syndrome, Hashimoto’s thyroiditis, idiopathic pulmonary
  • detection of the dendrimer conjugate in the image representation is indicative of one or more sites of neuroinflammation in the central nervous system of the subject.
  • the one or more sites of neuroinflammation in the central nervous system of the subject are associated with a neurodegenerative disorder.
  • the neurodegenerative disorder is selected from the group consisting of amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease.
  • the neurodegenerative disorder is multiple sclerosis (MS).
  • the neurodegenerative disorder is relapsing remitting MS, primary progressive MS, or secondary progressive MS.
  • the one or more sites of inflammation in the tissue of the subject are associated with a mechanism of macrophage activation, such as macrophage activation syndrome.
  • the one or more sites of inflammation in the tissue of the subject are associated with multi-organ dysfunction, such as neuroinflammation.
  • the one or more sites of inflammation in the tissue of the subject are associated with over-reactive M1 macrophages and/or elevations in proinflammatory markers such as IL-6, CRP, ferritin, and IL-1b.
  • the one or more sites of inflammation in the tissue of the subject are associated with inflammation characterized by cytokine storm.
  • detection of the dendrimer conjugate in the image representation is indicative of one or more cancer cells in the tissue of the subject.
  • the one or more cancer cells comprise tumor-associated macrophages.
  • the one or more cancer cells comprise primary tumor cells or metastasized cancer cells.
  • detection of the dendrimer conjugate in the image representation is indicative of a cancer in the tissue of the subject.
  • the cancer is of a type as described herein, such as brain cancer, breast cancer, ovarian cancer, uterine cancer, prostate cancer, testicular germ cell tumor, gastric cancer, esophagus cancer, lung cancer, liver cancer, renal cell cancer, or colon cancer.
  • the image representation is obtained by imaging the subject with a molecular imaging device.
  • the molecular imaging device comprises a gamma camera for positron emission tomography (PET) scanning or single photon emission computed tomography (SPECT).
  • PET positron emission tomography
  • SPECT single photon emission computed tomography
  • the dendrimer conjugate, or composition thereof is administered to the subject systemically. In certain embodiments, the dendrimer conjugate, or composition thereof, is administered to the subject intraperitoneally, intravenously, intrathecally, intratumorally, or orally.
  • a gamma camera calibrated for the gamma ray energy of the radionuclide component of the conjugate is used to image areas of uptake of the conjugate and quantify the amount of radioactivity present in the site. Imaging of the site in vivo can take place in a matter of a few minutes. However, imaging can take place, if desired, in hours or even longer, after the radiolabeled dendrimer composition is administered into a patient. In some embodiments, a sufficient amount of the 107/156 13813260 administered dose will accumulate in the area to be imaged within about 0.1 of an hour to permit the taking of scintiphotos.
  • Methods of Treating Cancer [00317] Provided herein are methods of treatment using the dendrimer conjugates disclosed herein.
  • methods of treating a cancer in a subject comprising administering a dendrimer conjugate disclosed herein or composition thereof to a subject.
  • the subject has a primary tumor and/or a metastasized cancer.
  • the subject has a brain tumor and/or brain metastasis.
  • the subject has a primary tumor and/or a metastasized cancer. In some embodiments, the subject has a brain tumor and/or brain metastasis. [00318] In some embodiments, a subject to be treated has a benign or malignant tumor. In some embodiments, the dendrimer conjugate or composition thereof delays or inhibits the growth of a tumor in a subject, reduces the growth or size of the tumor, inhibits or reduces metastasis of the tumor, and/or inhibits or reduces symptoms associated with tumor development or growth.
  • Exemplary tumor cells include tumor cells of cancers, including leukemias including, but not limited to, acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemias such as myeloblastic, promyelocytic, myelomonocytic, monocytic, erythroleukemia leukemias and myelodysplastic syndrome, chronic leukemias such as, but not limited to, chronic myelocytic (granulocytic) leukemia, chronic lymphocytic leukemia, hairy cell leukemia; polycythemia vera; lymphomas such as, but not limited to, Hodgkin’s disease, non-Hodgkin’s disease; multiple myelomas such as, but not limited to, smoldering multiple myeloma, nonsecretory myeloma, osteosclerotic myeloma, plasma cell leukemia, solitary plasmacytoma and extramedullary
  • a method of treating a cancer in a subject comprises administering a dendrimer conjugate or composition thereof to a subject, where the dendrimer conjugate comprises one or more radionuclides according to the dendrimer conjugates of the disclosure.
  • Suitable radionuclides include both ⁇ -particle and ⁇ -particle emitters.
  • the one or more radionuclides are selected from 90 Y, 131 I, 153 Sm, 166 Ho, 177 Lu, 186 Re, 203 Pb, 211 At, 212 Pb, 223 Ra, 225 Ac, and 227 Th, or ion thereof.
  • the one or more radionuclides comprise 90 Y.
  • the one or more radionuclides comprise 225 Ac, 203 Pb, or 177 Lu. In some embodiments, the one or more radionuclides comprise 225 Ac. In some embodiments, the one or more radionuclides comprise 203 Pb. In some embodiments, the one or more radionuclides comprise 177 Lu. [00321] In some embodiments, a radionuclide-conjugated dendrimer is further conjugated to one or more anti-tumor drugs.
  • anti-tumor drugs include STING agonists, CSF1R inhibitors, PARP inhibitors, VEGFR tyrosine kinase inhibitors, EGFR tyrosine kinase inhibitors, MEK inhibitors, glutaminase inhibitors, TIE II antagonists, and CXCR2 inhibitors.
  • Exemplary anti-tumor drugs also include Idarubicin, imatinib, irinotecan, exemestane, etoposide, epirubicin, oxaliplatin, octreotide, capecitabine, carboplatin, carmofur, cladribine, clarithromycin, gefitinib, gemcitabine, cyclophosphamide, cisplatin, cytarabine, zinostatin, cetuximab, tamoxifen, daunorubicin, dacarbazine, dactinomycin, tegafur, topotecan, toremifene, doxifluridine, doxorubicin, docetaxel, nimustine, docetaxel, paclitaxel, vincristine, vindensine, vinblastine, nedaplatin, pirarubicin, fluorouracil, flutamide
  • anti-tumor drugs include inhibitors targeting one or more of EGFR, ERBB2, VEGFRs, Kit, PDGFRs, ABL, SRC and mTOR.
  • one or more anti-tumor drugs are inhibitors such as crizotinib, ceritinib, alectinib, brigatinib, bosutinib, 110/156 13813260 dasatinib, imatinib, nilotinib, vemurafenib, dabrafenib, ibrutinib, palbociclib, sorafenib, ribociclib, cabozantinib, gefitinib, erlotinib, lapatinib, vandetanib, afatinib, osimertinib, ruxolitinib, tofacitinib, trametinib, axitin
  • one or more anti- tumor drugs are tyrosine kinase inhibitors such as HER2 inhibitors, EGFR tyrosine kinase inhibitors.
  • tyrosine kinase inhibitors include gefitinib, erlotinib, afatinib, dacomitinib, and osimertinib.
  • the dendrimer conjugate, or composition thereof is administered to the subject systemically. In certain embodiments, the dendrimer conjugate, or composition thereof, is administered to the subject intraperitoneally, intravenously, intrathecally, intratumorally, or orally.
  • Radiotherapeutic compounds Proper dose schedules for such radiotherapeutic compounds are known to those skilled in the art.
  • the compounds can be administered using many methods including, but not limited to, a single or multiple IV or IP injections, using a quantity of radioactivity that is sufficient to cause damage or ablation of the targeted tissue, but not so much that substantive damage is caused to non-target (normal tissue).
  • the quantity and dose required is different for different constructs, depending on the energy and half-life of the isotope used, the degree of uptake and clearance of the agent from the body and the mass of the target tissue.
  • doses can range from a single dose of about 30-50 mCi to a cumulative dose of up to about 3 Ci.
  • the radiotherapeutic compositions can include physiologically acceptable buffers and can require radiation stabilizers to prevent radiolytic damage to the compound prior to injection. Radiation stabilizers are known to those skilled in the art, and can include, for example, para-aminobenzoic acid, ascorbic acid, gentisic acid, and the like.
  • Controls [00327] The effect of the dendrimer/agent compositions, optionally including one or more additional active agents can be compared to a control. Suitable controls are known in the art and include, for example, an untreated subject, or a placebo-treated subject. A typical control is a comparison of a condition or symptom of a subject prior to and after administration of the targeted agent.
  • the condition or symptom can be a biochemical, molecular, physiological, or pathological readout.
  • the effect of the dendrimer/agent composition on a particular symptom, pharmacologic, or physiologic indicator can be compared to an untreated subject, or the condition of the subject prior to treatment.
  • the symptom, 111/156 13813260 pharmacologic, or physiologic indicator is measured in a subject prior to treatment, and again one or more times after treatment is initiated.
  • the control is a reference level, or average determined based on measuring the symptom, pharmacologic, or physiologic indicator in one or more subjects that do not have the disease or condition to be treated (e.g., healthy subjects).
  • the effect of the treatment is compared to a conventional treatment that is known the art.
  • an untreated control subject suffers from the same disease or condition as the treated subject.
  • Dosages and Effective Amounts are dependent on the severity and location of the disorder or condition and/or methods of administration, and can be determined by those skilled in the art.
  • the active agents do not target or otherwise modulate the activity or quantity of healthy cells not within or associated with the diseased/damaged tissue, or do so at a reduced level compared to cells associated with the inflammation or of the tumor region. In this way, by-products and other side effects associated with the compositions are reduced.
  • a pharmaceutical composition including a therapeutically effective amount of the dendrimer compositions and a pharmaceutically acceptable diluent, carrier or excipient is described.
  • the pharmaceutical compositions include an effective amount of hydroxyl-terminated PAMAM dendrimers conjugated to one or more radionuclides.
  • the radiotherapy or imaging dose will be determined from clinical studies of subjects with varying degrees of inflammation and/or tumor sizes to determine the optimal dose range.
  • Dosage forms of the pharmaceutical composition including the dendrimer compositions are also provided. “Dosage form” refers to the physical form of a dose of a therapeutic compound, such as a capsule or vial, intended to be administered to a patient.
  • the term “dosage unit” refers to the amount of the therapeutic compounds to be administered to a patient in a single dose.
  • the actual effective amounts of dendrimer conjugate can vary according to factors including the specific active agent administered, the particular composition formulated, the mode of administration, and the age, weight, condition of the subject being treated, as well as the route of administration and the disease or disorder. In some embodiments, the subjects are humans. Generally, the dosage may be lower for intravenous injection or infusion. 112/156 13813260 [00333] In general, the timing and frequency of administration will be adjusted to balance the efficacy of a given treatment or diagnostic schedule with the side effects of the given delivery system.
  • Exemplary dosing frequencies include continuous infusion, single and multiple administrations such as hourly, daily, weekly, monthly or yearly dosing.
  • dosages of dendrimer compositions are administered once, twice, or three times daily, or every other day, two days, three days, four days, five days, or six days to a human.
  • dosages are administered about once or twice every week, every two weeks, every three weeks, or every four weeks.
  • dosages are administered about once or twice every month, every two months, every three months, every four months, every five months, or every six months.
  • a dosing regimen can be any length of time sufficient to treat the disorder in the subject.
  • the regimen includes one or more cycles of a round of therapy followed by a drug holiday (e.g., no drug).
  • the drug holiday can be 1, 2, 3, 4, 5, 6, or 7 days; or 1, 2, 3, 4 weeks, or 1, 2, 3, 4, 5, or 6 months.
  • Kits [00336]
  • the disclosure provides a kit comprising a dendrimer conjugate or composition described herein.
  • the kit comprises a single dose or a plurality of doses of a composition comprising a dendrimer conjugate of the disclosure, and instructions for administering the composition.
  • the instructions direct that an effective amount of the composition be administered to an individual with a particular condition/disease as indicated and in accordance with the disclosure.
  • a kit comprises one or more containers, such as a vial, test tube, flask, bottle, syringe, or other container means into which a component may be placed, where at least one container comprises a composition of the disclosure.
  • the kit comprises a single container comprising a composition of the disclosure.
  • the kit comprises two or more (e.g., 2, 3, 4, 5, or more) containers comprising the composition.
  • the components of a kit are packaged in solution or lyophilized form.
  • the kit comprises at least one container comprising the composition in lyophilized form, and at least one container comprising a liquid component for reconstituting the composition in solution form.
  • the kit comprises at 113/156 13813260 least one container comprising one or more stabilizers, bulking agents (e.g., mannitol), or other additives known in the art.
  • the GC conditions used for Examples 1 and 2 below are as provided herein.
  • the chromatographic conditions include: Column: Agilent CP-Volamine (Part number CP7447) Inlet Temperature: 250 o C Inlet Pressure: 14.3 psi Inlet Total flow: 37.3 mL/min Inlet Split Ratio: 10:1 Injection Volume: 5 mL Column Flowrate: 3.1 mL/min FID Temperature: 300 o C FID H2 Flow: 40.0 mL/min FID Air Flow: 360.0 mL/min FID Makeup Flow: 25 mL/min FID Lit Offset: 0.5 pA Run Time: 20.33 min The oven temperature gradient used is: 114/156 13813260
  • Example 1 Synthesis of PAMAM G4-OH-Alkyne 3 115/156 13813260
  • a 1-Liter jacketed vessel was charged with a 9.42:1 molar ratio of ethanolamine and PEG-Alkyne (e.g., Ambeed, Lot# 100902012-002230BFY) followed by methanol.
  • the vessel was purged with N2(g) and cooled to 0 °C.
  • a 10wt% of PAMAM G3.5 (e.g., Dentritech, lot# 0121-02-E3.5-LD-A) in methanol was then added over 2 hours to the reactor. The solution was then stirred for 2 hours at 0 °C before warming to 20 °C. The solution was then allowed to stir at 20 °C for 6 days.
  • a 5-Liter jacketed vessel was charged with a 2.23:1 molar ratio of ethanolamine and PEG-Alkyne (e.g., Ambeed, Lot# 100902012-002230BFY) followed by methanol.
  • the vessel was purged with N 2 (g) and cooled to 0 °C.
  • a 10wt% of PAMAM G3.5 e.g., Dentritech, lot# 0121-02-E3.5-LD-A
  • the solution was then stirred for 2 hours at 0 °C before warming to 20 °C.
  • the solution was then allowed to stir at 20 °C for 6 days.
  • the reaction was then stirred for 2 hours at 20 °C.
  • the residual copper was removed by stirring 4 equivalents (relative to copper loading) of Silicycle SiliaMetS TAAcONa scavenger at 20 °C for 4 hours.
  • the solution was subjected to purification by ultrafiltration.
  • the solution was frozen, and water removed by lyophilization providing the product as a light-yellow foam.
  • a small sample of the foam was taken for analysis by 1 H-NMR and 13 C-NMR to determine the degree of alkyne functionalization.
  • the remaining solid was dissolved in pure ethanol to generate a 16.3 wt% ethanolic solution.
  • Procedure A1 can be used to synthesize the precursor to -R B -L 2 -R 1 in Formulae (I′), (I), (II′), and (II) wherein the tetrazine in Procedure A1 is reacted to ultimately form one of the polycyclic rings in R B .
  • the compounds in FIG.29A may be synthesized via Procedure A1 and used throughout Example 5 and 6.
  • Tri-tert- butyl 2,2',2''-(10-(2-((4-(6-methyl-1,2,4,5-tetrazin-3-yl)benzyl)amino)-2-oxoethyl)-1,4,7,10- tetraazacyclododecane-1,4,7-triyl)triacetate (200 mg, 0.26 mmol) was dissolved in dichloromethane (4 mL), and trifluoroacetic acid (4 mL) was added. The reaction mixture was stirred at room temperature overnight while protecting from light.
  • reaction mixture was concentrated and dried under vacuum to afford 2,2',2''-(10-(2-((4-(6-methyl-1,2,4,5-tetrazin-3- yl)benzyl)amino)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (13) as a bright pink solid.
  • Procedure A2 can be utilized to synthesize a variety of moieties comprising a chelator which are ready for further functionalization. Procedure A2 can be used to synthesize the precursor to -R B -L 2 -R 1 in Formulae (I′), (I), (II′), and (II) wherein an azide installed in Procedure A2 is reacted to ultimately form one of the polycyclic rings in R B .
  • Procedure B1 can be utilized to synthesize a variety of dendrimers comprising a chelator.
  • Procedure B1 can be used to synthesize compounds of Formulae (I′), (I), (II′), and (II), such as by reacting a tetrazine moiety as synthesized in Procedure A1 with TCO to form the polycyclic moiety R B in Formulae (I′), (I), (II′), and (II).
  • D5.5-CO2Me (3) D5.5-CO2Me (3).
  • D6-OH-3-NH2 (6) (4.0 grams, 0.068 mmol, 90% yield).
  • D6-OH-3-TCO (8) To a reaction vessel was added DIEA (14 mg, 0.11 mmol) and a solution of D6-OH-3-NH2 (6) (537 mg, 0.00917 mmol) in DMAc (5 mL). A solution of TCO- PEG3-NHS ester (7) in DMAc (2 mL) was then added dropwise over 2 minutes. The reaction was allowed to stir at room temperature for 24 hours protected from light. The reaction was then diluted with water (10x).
  • D6-OH-3-TCO (8) (526 mg, 0.00882 mmol, 96% yield).
  • D6-OH-3-NOTA 10 (also referred to as S08NT3M).
  • D6-OH-3-TCO (8) (244 mg, 0.00393 mmol) was dissolved in water (5 mL).
  • NOTA-Tetrazine.3TFA 9 (12 mg, 0.020 mmol) was added and the resulting solution was stirred at room temperature for 30 minutes.
  • D6-OH-3-TCO (8) (110 mg, 0.00188 mmol) was dissolved in water (5 mL).
  • DOTA-Tetrazine.3TFA (13) (5.4 mg, 0.0092 mmol) was added and the resulting solution was stirred at room temperature for 30 minutes.
  • the reaction was diluted with H2O (40 mL).
  • the low molecular weight impurities were removed using tangential flow filtration (TFF) (10 kDa membrane).
  • TMF tangential flow filtration
  • the resulting aqueous retentate was frozen and the water was removed through lyophilization to give D6-OH-3- DOTA (14) (110 mg, 0.00179 mmol, 95% yield).
  • D5-OH-2-NOTA (16) also referred to as V01NT3M2).
  • D5-OH-2-TCO (15) (synthesized analogously to (8)) (309 mg, 0.0103 mmol) was dissolved in water (10 mL).
  • NOTA-Tetrazine.3TFA (9) (16 mg, 0.026 mmol) was added and the resulting solution was stirred at room temperature for 30 minutes.
  • the reaction was diluted with H2O (40 mL).
  • the low molecular weight impurities were removed using tangential flow filtration (TFF) (5 kDa membrane).
  • D4-OH-1-NOTA (also referred to as H101NT3M1).
  • D4-OH-1-TCO (17) (synthesized analogously to (8)) (173 mg, 0.0118 mmol) was dissolved in water (5 mL).
  • NOTA-Tetrazine.3TFA (9) (7.1 mg, 0.012 mmol) was added and the resulting solution was 126/156 13813260 stirred at room temperature for 30 minutes. The reaction was diluted with H2O (40 mL).
  • D4-OH-1-NOTA (18) (167 mg, 0.0110 mmol, 93% yield).
  • D4-OH-3-NOTA (20).
  • D4-OH-3-TCO (19) (synthesized analogously to (8)) (135 mg, 0.00865 mmol) was dissolved in water (5 mL).
  • NOTA-Tetrazine.3TFA (9) (16 mg, 0.027 mmol) was added and the resulting solution was stirred at room temperature for 30 minutes.
  • Procedure B2 can be used to synthesize compounds of Formulae (I′), (I), (II′), and (II), such as by reacting an azide moiety as synthesized in Procedure A2 with DBCO to form the polycyclic moiety R B in Formulae (I′), (I), (II′), and (II).
  • Procedure B2 can be used to synthesize compounds of Formulae (I′), (I), (II′), and (II), such as by reacting an azide moiety as synthesized in Procedure A2 with DBCO to form the polycyclic moiety R B in Formulae (I′), (I), (II′), and (II).
  • 127/156 13813260 [00369]
  • D6-OH-5-NH2 (41).
  • NH2-PEG2-NH2 (1.75 grams, 11.8 mmol) and MeOH (30 mL).
  • D6-OH-5-DBCO 43) (900 mg, 0.015 mmol, 94% yield).
  • D6-OH-5-DOTA 45.
  • D6-OH-5-DBCO (43) 115 mg, 0.00188 mmol was dissolved in DMAc (1.5 mL).
  • a solution of DOTA-PEG5-azide.3TFA (44) 7.0 mg, 0.095 mmol was added and the resulting solution was stirred at room temperature for 4 hours. The reaction was then diluted with 16% wt/wt DMAc/water (50x).
  • Example 6 Radiolabeling (Procedure C Synthesis)
  • the routes outlined in Example 6 can be used to chelate a radionuclide to any one of the chelators as provided herein (i.e., to transform a compound of Formula (I′) or (II′), wherein R 1 is a chelator of a radionuclide, to a compound of Formula (I) or (II), wherein R 1 is a chelator comprising a radionuclide).
  • D6-OH-3-NOTA-64Cu (32).
  • the resulting solution was treated with 64 CuCl2 for 60 minutes at 37C to give D6-OH-3-NOTA-64Cu (32).97.1% 64 Cu labeling as determined by radio-HPLC (C-18).
  • D6-OH-3-NODAGA-64Cu 33).
  • the resulting solution was treated with 64 CuCl2 for 60 minutes at 37C to give D6-OH-3-NODAGA-64Cu (33).11.0% 64 Cu labeling as determined by radio-HPLC (C-18).
  • D6-OH-3-NODAGA-177Lu 39.
  • the resulting solution was treated with 177LuCl 3 for 60 minutes at 75C to give D6-OH-3-NODAGA-177Lu (39).
  • D6-OH-3-DOTA-64Cu 34. Synthesis according to Procedure C, for example, following the procedure of D6-OH-3-NODAGA-64Cu (33).
  • D6-OH-3-DOTA-177Lu 40.
  • the resulting solution was treated with 177 LuCl3 for 60 minutes at 75C to give D6-OH-3-DOTA-177Lu (39).98.3% 177 Lu labeling as determined by radio-HPLC (C-18).
  • D5-OH-2-NOTA-64Cu 35).
  • D4-OH-3-NOTA-64Cu (37).
  • the resulting solution was treated with 64 CuCl2 for 120 minutes at 37C to give D6-OH-3-NOTA-64Cu (37).64% 64 Cu incorporation was obtained as determined by radio-HPLC (C-18).
  • Example 7 Targeting Tumor Associated Macrophages
  • Two hydroxylated dendrimer (HD) sizes G6 and G5, ⁇ 30 kDa) with NOTA covalently linked to surface hydroxyls and chelated to 64 Cu were used to evaluate in vivo tumor associated macrophages (TAM) uptake in a triple negative breast cancer (4T1) xenograft model.
  • TAM tumor associated macrophages
  • Two HDs were synthesized using metal free water.
  • One HD (G5) was produced with two NOTA arms (HD5-NOTA (also referred to as V01NT3M2 and D5-OH-2-NOTA (16))).
  • HD6-NOTA also referred to as S08NT3M and D6-OH-3-NOTA (10)
  • Both compounds were radiolabeled with 64 Cu.
  • HD5 and HD6 were labeled with Cy5 (HD5-Cy5 (also referred to as V02CY0M2); HD6-Cy5 (also referred to as S09CY0M3)).
  • Cy5 HD5-Cy5 (also referred to as V02CY0M2)
  • HD6-Cy5 also referred to as S09CY0M3
  • In vivo biodistribution was determined in female Balb/c mice with and without implantation of 4T1 cells.
  • mice After tumors reached a mean size of 100 mm 3 , animals (4/group) were balanced by tumor size across groups to receive an 10 MBq IV dose of 157 or 16 MBq/mg of 64 Cu-HD5-NOTA, or 182 or 20 MBq/mg of 64 Cu-HD6-NOTA. The same doses were administered to two groups of control mice without tumors (4/group). PET scans were conducted at 2, 24, and 48 h post-dose with regions of interest (ROIs) of kidney, liver, bladder and tumor (FIGs.1-18). Following the last scan, mice were administered with Cy5 labelled HD (HD5-Cy5 or HD6-Cy5) and then sacrificed 24 h later.
  • ROIs regions of interest
  • Tumor uptake was greater for the 64 Cu-HD6-NOTA (also referred to herein as [ 64 Cu]Cu-S08NT3M and D6-OH-3-NOTA-64Cu (32)) than the 64 Cu-HD5-NOTA (also referred to as [ 64 Cu]Cu-V01NT3M2 and D5-OH-2-NOTA-64Cu (35)) at 24 and 48 h post-dose (15.6 vs 2.3%ID/g, 24 h; 14.4 vs 1.7%ID/g, 48 h) for the higher specific activity doses.
  • the initial kidney uptake was higher for the high specific activity of 64 Cu-HD5-NOTA than 64 Cu-HD6-NOTA due to predominantly renal clearance ( 64 Cu-HD5-NOTA exhibited low liver uptake (2H: 3.5%ID/g, 48H: 2.5%ID/g), and kidney (2H: 13.4%ID/g, 48H:2.0-2.2%ID/g) and bladder (2H: 216.9%ID/g, 48H:0.9%ID/g) uptake).
  • 64 Cu-HD6-NOTA had lower renal clearance with more liver uptake (2H: 13.2%ID/g, 48H: 10.6%ID/g) suggesting biliary clearance.
  • 64 Cu-HD6-NOTA is a first in class tumor imaging agent targeting TAMs that exist across many different cancers.
  • the present disclosure includes embodiments in which more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process. 132/156 13813260 [00387] Furthermore, the present disclosure encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims is introduced into another claim. For example, any claim that is dependent on another claim can be modified to include one or more limitations found in any other claim that is dependent on the same base claim. Where elements are presented as lists, e.g., in Markush group format, each subgroup of the elements is also disclosed, and any element(s) can be removed from the group.

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Abstract

L'invention concerne des conjugués de dendrimères de formules (F), (I), (IP) et (II), ainsi que des compositions les comprenant. L'invention concerne en outre des procédés d'utilisation des conjugués dendrimères et des compositions, notamment en tant qu'agents d'imagerie.
PCT/US2025/023748 2024-04-08 2025-04-08 Conjugués de dendrimères et leurs procédés d'utilisation Pending WO2025217220A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011053618A2 (fr) * 2009-10-30 2011-05-05 The Regents Of The University Of Michigan Dendrimères à terminaison hydroxyle
US9345781B2 (en) * 2009-12-11 2016-05-24 The Regents Of The University Of Michigan Targeted dendrimer-drug conjugates
US20230398241A1 (en) * 2020-10-30 2023-12-14 Ashvattha Therapeutics, Inc. Radiolabeled ether dendrimer conjugates for pet imaging and radiotherapy
US20240058459A1 (en) * 2019-12-04 2024-02-22 Ashvattha Therapeutics, Inc. Dendrimer compositions and methods for drug delivery to the eye

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011053618A2 (fr) * 2009-10-30 2011-05-05 The Regents Of The University Of Michigan Dendrimères à terminaison hydroxyle
US9345781B2 (en) * 2009-12-11 2016-05-24 The Regents Of The University Of Michigan Targeted dendrimer-drug conjugates
US20240058459A1 (en) * 2019-12-04 2024-02-22 Ashvattha Therapeutics, Inc. Dendrimer compositions and methods for drug delivery to the eye
US20230398241A1 (en) * 2020-10-30 2023-12-14 Ashvattha Therapeutics, Inc. Radiolabeled ether dendrimer conjugates for pet imaging and radiotherapy

Non-Patent Citations (1)

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Title
KHARWADE ET AL.: "Starburst pamam dendrimers: Synthetic approaches, surface modifications, and biomedical applications", ARABIAN JOURNAL OF CHEMISTRY, vol. 13, 13 May 2020 (2020-05-13), pages 6009 - 6039, XP086204624, DOI: 10.1016/j.arabjc.2020.05.002 *

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