Radiolabeled dendrimer conjugates and methods of use thereof

Abstract

Provided herein are dendrimer conjugates of Formulae (F), (I), (IP), and (II), as well as compositions comprising the same. Further provided are methods of using the dendrimer conjugates and compositions, including as imagining agents.

Description

RADIOLABELED DENDRIMER CONJUGATES AND METHODS OF USE THEREOF RELATED APPLICATIONS

[0001] This application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Patent Application U.S.S.N.63 / 631,163, filed April 8, 2024, which is incorporated herein by reference in its entirety. BACKGROUND

[0002] Molecular imaging has allowed for in vivo real-time visualization, characterization, and measurement of biological processes at the molecular and cellular levels. Various molecular imaging modalities have been developed, including magnetic resonance imaging (MRI), optical imaging, positron emission tomography (PET), and single photon emission computed tomography (SPECT). 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

[0003] 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.

[0004] In one aspect, provided herein are dendrimer conjugates of Formula (I′):or a pharmaceutically acceptable salt thereof, wherein D is a dendrimer, R1is a radionuclide or a chelator of a radionuclide, and Z, R1, q, m, n, and p are as defined herein. In some embodiments, a compound of Formula (I′) is of Formula (I). In one aspect, provided herein are dendrimer conjugates of Formula (I): 1 / 156 13813260or a pharmaceutically acceptable salt thereof, wherein D is a dendrimer, R1is a radionuclide or a chelator comprising a radionuclide, and Z, R1, q, m, n, and p are as defined herein. In some embodiments, the dendrimer, D, is a PAMAM dendrimer. In certain embodiments, the dendrimer is a generation 4 PAMAM dendrimer. In some embodiments, R1is18F,89Zr,90Y, or177Lu. In some embodiments, the compound of Formula (I) is of the formula:, or a pharmaceutically acceptable salt thereof, wherein D is a generation 4 PAMAM dendrimer.

[0005] In another aspect, provided herein are dendrimer conjugates of Formula (II′):or a pharmaceutically acceptable salt thereof, wherein D is a dendrimer, R1is a radionuclide or a chelator of a radionuclide, and RA, RB, L1, L2, m, n, and p are as defined herein. In some embodiments, the compound of Formula (II) is of Formula (II′). In another aspect, provided herein are dendrimer conjugates of Formula (II):or a pharmaceutically acceptable salt thereof, wherein D is a dendrimer, R1is a radionuclide or a chelator comprising a radionuclide, and RA, RB, L1, L2, m, n, and p are as defined herein. In some embodiments, the dendrimer, D, is a PAMAM dendrimer. In certain embodiments, the dendrimer is a generation 4 or 6 PAMAM dendrimer. In some embodiments, RAis:2 / 156 13813260some embodiments, R1is18F,89Zr,90Y, or177Lu. In some embodiments, R1is DOTA (e.g., chelated to111In or90Y) or NOTA (e.g., chelated to64Cu). In some embodiments, the dendrimer conjugate of Formula (II) is of the formula:, or 3 / 156 13813260, or a pharmaceutically acceptable salt thereof.

[0006] In a further 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.

[0007] In another aspect, 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.

[0008] In a further aspect, provided herein are 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. In some embodiments, 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. BRIEF DESCRIPTION OF THE DRAWINGS

[0009] FIG.1 shows representative PET / CT images from 2H, 24H, and 48H after injection of [64Cu]Cu-V01NT3M2160 MBq / mg. Left: axial images sectioned at tumor. Middle: coronal image sectioned at kidney and tumor. Right: maximum intensity projection (MIP).

[0010] FIG.2 shows representative PET / CT images from 2H, 24H, and 48H after injection of [64Cu]Cu-V01NT3M216 MBq / mg. Left: axial images sectioned at tumor. Middle: coronal image sectioned at kidney and tumor. Right: maximum intensity projection (MIP).

[0011] FIG.3 shows representative PET / CT images from 2H, 24H, and 48H after injection of [64Cu]Cu-S08NT3M3200 MBq / mg. Left: axial images sectioned at tumor. Middle: coronal image sectioned at kidney and tumor. Right: maximum intensity projection (MIP). 4 / 156 13813260

[0012] FIG.4 shows representative PET / CT images from 2H, 24H, and 48H after injection of [64Cu]Cu-S08NT3M320 MBq / mg. Left: axial images sectioned at tumor. Middle: coronal image sectioned at liver. Right: maximum intensity projection (MIP).

[0013] FIG.5 shows representative PET / CT images from 2H, 24H, and 48H after injection of [64Cu]Cu-S08NT3M320 MBq / mg. Left: axial images sectioned at tumor. Middle: coronal image sectioned at kidney and tumor. Right: maximum intensity projection (MIP).

[0014] FIG.6 shows representative PET / CT images from 2H, 24H, and 48H after injection of [64Cu]Cu-V01NT3M2160 MBq / mg. Left: axial images sectioned at bladder. Middle: coronal image sectioned at kidney. Right: maximum intensity projection (MIP).

[0015] FIG.7 shows representative PET / CT images from 2H, 24H, and 48H after injection of [64Cu]Cu-S08NT3M3200 MBq / mg. Left: axial images sectioned at bladder Middle: coronal image sectioned at kidney. Right: maximum intensity projection (MIP).

[0016] FIG.8 shows representative PET / CT images from 2H, 24H, and 48H after injection of [64Cu]Cu-V01NT3M2160 MBq / mg. Left: axial images sectioned at tumor. Middle: coronal image sectioned at kidney and tumor. Right: maximum intensity projection (MIP).

[0017] FIG.9 shows representative PET / CT images from 2H, 24H, and 48H after injection of [64Cu]Cu-V01NT3M216 MBq / mg. Left: axial images sectioned at tumor. Middle: coronal image sectioned at kidney and tumor. Right: maximum intensity projection (MIP).

[0018] FIG.10 shows representative PET / CT images from 2H, 24H, and 48H after injection of [64Cu]Cu-S08NT3M3200 MBq / mg. Left: axial images sectioned at tumor. Middle: coronal image sectioned at kidney and tumor. Right: maximum intensity projection (MIP).

[0019] FIG.11 shows representative PET / CT images from 2H, 24H, and 48H after injection of [64Cu]Cu-S08NT3M320 MBq / mg. Left: axial images sectioned at tumor. Middle: coronal image sectioned at liver. Right: maximum intensity projection (MIP).

[0020] FIG.12 shows representative PET / CT images from 2H, 24H, and 48H after injection of [64Cu]Cu-S08NT3M320 MBq / mg. Left: axial images sectioned at tumor. Middle: coronal image sectioned at kidney and tumor. Right: maximum intensity projection (MIP).

[0021] FIG.13 shows representative PET / CT images from 2H, 24H, and 48H after injection of [64Cu]Cu-V01NT3M2160 MBq / mg. Left: axial images sectioned at bladder. Middle: coronal image sectioned at kidney. Right: maximum intensity projection (MIP).

[0022] FIG.14 shows representative PET / CT images from 2H, 24H, and 48H after injection of [64Cu]Cu-S08NT3M3200 MBq / mg. Left: axial images sectioned at bladder. Middle: coronal image sectioned at kidney. Right: maximum intensity projection (MIP). 5 / 156 13813260

[0023] FIG.15 shows representative PET / CT images from 2H, 24H, and 48H after injection of [64Cu]Cu-S08NT3M3200 MBq / mg. Left: axial images sectioned at tumor. Middle: coronal image sectioned at kidney and tumor. Right: maximum intensity projection (MIP).

[0024] FIG.16 shows representative PET / CT images from 2H, 24H, and 48H after injection of [64Cu]Cu-S08NT3M320 MBq / mg. Left: axial images sectioned at tumor. Middle: coronal image sectioned at liver. Right: maximum intensity projection (MIP).

[0025] FIG.17 shows representative PET / CT images from 2H, 24H, and 48H after injection of [64Cu]Cu-S08NT3M320 MBq / mg. Left: axial images sectioned at tumor. Middle: coronal image sectioned at kidney and tumor. Right: maximum intensity projection (MIP).

[0026] FIG.18 shows representative PET / CT images from 2H, 24H, and 48H after injection of [64Cu]Cu-S08NT3M3200 MBq / mg. Left: axial images sectioned at bladder. Middle: coronal image sectioned at kidney. Right: maximum intensity projection (MIP).

[0027] FIG.19 shows a graph demonstrating the in vivo biodistribution of64Cu-labelled compound post iv injection at 2 hours. Bars represent mean SEM, n=4 / group.

[0028] FIG.20 shows a graph demonstrating the in vivo biodistribution of64Cu-labelled compound post iv injection at 24 hours. Bars represent mean SEM, n=4 / group.

[0029] FIG.21 shows a graph demonstrating the in vivo biodistribution of64Cu-labelled compound post iv injection at 48 hours. Bars represent mean SEM, n=4 / group.

[0030] FIG.22 shows a graph demonstrating the in vivo biodistribution of64Cu-labelled compound in bladder post iv injection at 2, 4 and 48H. Bars represent mean SEM, n=4 / group.

[0031] FIG.23 shows a graph demonstrating the in vivo biodistribution of64Cu-labelled compound in liver post iv injection at 2, 4 and 48H. Bars represent mean SEM, n=4 / group.

[0032] FIG.24 shows a graph demonstrating the in vivo biodistribution of64Cu-labelled compound in tumor post iv injection at 2, 4 and 48H. Bars represent mean SEM, n=4 / group.

[0033] FIG.25 shows a graph demonstrating the in vivo biodistribution of64Cu-labelled compound in left kidney post iv injection at 2, 4 and 48H. Bars represent mean SEM, n=4 / group.

[0034] FIG.26 shows a graph demonstrating the in vivo biodistribution of64Cu-labelled compound in right kidney post iv injection at 2, 4 and 48H. Bars represent mean SEM, n=4 / group.

[0035] FIG.27 shows a graph demonstrating the ex vivo biodistribution of64Cu-labelled compounds 72H post iv injection. Bars represent mean ±SEM, n=4 / group. 6 / 156 13813260

[0036] 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 RBand 3 DOTA moieties. FIG.28E shows another DOTA dendrimer comprising a 3 PEG linker, bicyclic RB, and 5 DOTA moieties. FIG.28F shows yet another DOTA dendrimer comprising a 2 PEG linker, bicyclic RB, and 5 DOTA moieties. FIG.28G shows another DOTA dendrimer comprising a quadricyclic RBand 5 DOTA moieties. FIG.28H shows yet another DOTA dendrimer comprising a quadricyclic RBand 2 DOTA moieties.

[0037] 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 tetrazinefunctionalized chelators (i.e. ̧precursors to -RB-L2-R1 of Formulae (I′), (I), (II′), and (II)) thatcan 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 RB. FIG.29B shows exemplary R1of Formulae (I′) and (II′), pre-chelation to a radionuclide (i.e., resulting in Formulae (I) and (II) upon chelation). DETAILED DESCRIPTION OF THE INVENTION

[0038] Among other aspects, 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. In some embodiments, dendrimer conjugates of the disclosure selectively target activated microglia, sites of inflammation following systemic administration, and / or tumor-associated macrophages. In some embodiments, 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. In some embodiments, dendrimer conjugates of the disclosure provide stable PET imaging agents for non-invasive and specific imaging of a tissue. In some embodiments, dendrimer conjugates of the disclosure are therapeutically effective for treating neurological disorders, autoimmune disorders, and / or cancer.

[0039] In some aspects, the disclosure provides dendrimer conjugates comprising a hydroxyl- terminated dendrimer conjugated to a radionuclide, such as18F,64Cu,89Zr,90Y,111In,177Lu,203Pb, or225Ac, and methods of using the same for imaging a tissue in a subject. In some aspects, the disclosure provides methods of using dendrimer conjugates for diagnosing, detecting, and / or imaging one or more sites of inflammation in a subject. In some aspects, the 7 / 156 13813260disclosure provides methods of using dendrimer conjugates for diagnosing, detecting, and / or imaging one or more cancer cells in a subject. In some aspects, 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.

[0041] When a range of values (“range”) is listed, it encompasses each value and sub-range within the range. A range is inclusive of the values at the two ends of the range unless otherwise provided. For example,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.

[0042] The term “alkyl” refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 20 carbon atoms (“C1–20alkyl”). In some embodiments, an alkyl group has 1 to 12 carbon atoms (“C1–12 alkyl”). In some embodiments, an alkyl group has 1 to 10 carbon atoms (“C1–10alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms (“C1–9alkyl”). 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 (“C1–5alkyl”). In some embodiments, 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 (“C1–2alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“C1alkyl”). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C2-6alkyl”). Examples of C1–6alkyl 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 (C5) (e.g., n-pentyl, 3-pentanyl, amyl, neopentyl, 3-methyl-2-butanyl, tert-amyl), and hexyl (C6) (e.g., n-hexyl). Additional examples of 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). In certain embodiments, 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 13813260e.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)). In certain embodiments, the alkyl group is a substituted C1–12 alkyl (such as substituted C1–6 alkyl, e.g., –CH2F, –CHF2, –CF3, – CH2CH2F, –CH2CHF2, –CH2CF3, or benzyl (Bn)).

[0043] The term “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. In certain embodiments, a heteroalkyl group refers to a saturated group having from 1 to 20 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1–20alkyl”). 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”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 10 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1–10alkyl”). 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 (“heteroC1–9alkyl”). 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”). In some embodiments, 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 (“heteroC1–5alkyl”). 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 (“heteroC1–3alkyl”). In some embodiments, 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. In certain 9 / 156 13813260embodiments, the heteroalkyl group is an unsubstituted heteroC1–12alkyl. In certain embodiments, the heteroalkyl group is a substituted heteroC1–12 alkyl.

[0044] The term “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”). In some embodiments, an alkenyl group has 1 to 11 carbon atoms (“C1–11alkenyl”). In some embodiments, an alkenyl group has 1 to 10 carbon atoms (“C1–10alkenyl”). 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 (“C1–8alkenyl”). In some embodiments, an alkenyl group has 1 to 7 carbon atoms (“C1–7alkenyl”). In some embodiments, an alkenyl group has 1 to 6 carbon atoms (“C1–6 alkenyl”). In some embodiments, an alkenyl group has 1 to 5 carbon atoms (“C1–5 alkenyl”). In some embodiments, an alkenyl group has 1 to 4 carbon atoms (“C1–4alkenyl”). In some embodiments, an alkenyl group has 1 to 3 carbon atoms (“C1–3alkenyl”). 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 (“C1alkenyl”). 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 C1–6alkenyl groups include the aforementioned C2-4alkenyl 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. Unless otherwise specified, each instance of an alkenyl group is independently unsubstituted (an “unsubstituted alkenyl”) or substituted (a “substituted alkenyl”) with one or more substituents. In certain embodiments, the alkenyl group is an unsubstituted C1-20 alkenyl. In certain embodiments, the alkenyl group is a substituted C1-20alkenyl. In an alkenyl group, a C=C double bond for which the stereochemistry is not specified (e.g., −CH=CHCH3 ormay be in the (E)- or (Z)- configuration.

[0045] The term “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. In certain embodiments, a heteroalkenyl group refers to a group 10 / 156 13813260having from 1 to 20 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC1–20 alkenyl”). In certain embodiments, 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 (“heteroC1–12alkenyl”). 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 (“heteroC1–10alkenyl”). In some embodiments, a heteroalkenyl group has 1 to 9 carbon atoms at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC1–9alkenyl”). 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 (“heteroC1–7alkenyl”). In some embodiments, 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 (“heteroC1–5alkenyl”). 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”). In some embodiments, a heteroalkenyl group has 1 to 3 carbon atoms, at least one double bond, and 1 heteroatom within the parent chain (“heteroC1–3alkenyl”). 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 (“heteroC1–6alkenyl”). Unless otherwise specified, each instance of a heteroalkenyl group is independently unsubstituted (an “unsubstituted heteroalkenyl”) or substituted (a “substituted heteroalkenyl”) with one or more substituents. In certain embodiments, the heteroalkenyl group is an unsubstituted heteroC1–20alkenyl. In certain embodiments, the heteroalkenyl group is a substituted heteroC1–20 alkenyl.

[0046] The term “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 (“C1-9alkynyl”). In some embodiments, an alkynyl group has 1 to 8 carbon atoms (“C1-811 / 156 13813260alkynyl”). In some embodiments, an alkynyl group has 1 to 7 carbon atoms (“C1-7alkynyl”). 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 (“C1-4alkynyl”). 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”). In some embodiments, an alkynyl group has 1 carbon atom (“C1alkynyl”). In some embodiments, 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 (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. Examples of C1-6alkenyl groups include the aforementioned C2-4alkynyl 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. In certain embodiments, the alkynyl group is a substituted C1-20 alkynyl.

[0047] The term “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. In certain embodiments, 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”). In certain embodiments, 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 (“heteroC1–10alkynyl”). 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 (“heteroC1–9alkynyl”). 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”). In some embodiments, a heteroalkynyl group has 1 to 7 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC1–7alkynyl”). 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 13813260within the parent chain (“heteroC1–5alkynyl”). In some embodiments, 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 (“heteroC1–3alkynyl”). 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”). In some embodiments, a heteroalkynyl group has 1 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain (“heteroC1–6alkynyl”). 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 heteroC1–20alkynyl. In certain embodiments, the heteroalkynyl group is a substituted heteroC1–20 alkynyl.

[0048] The term “carbocyclyl” or “carbocyclic” refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 14 ring carbon atoms (“C3-14carbocyclyl”) and zero heteroatoms in the non-aromatic ring system. In some embodiments, a carbocyclyl group has 3 to 14 ring carbon atoms (“C3-14 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 13 ring carbon atoms (“C3-13carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 12 ring carbon atoms (“C3-12carbocyclyl”). In some embodiments, 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 (“C3-8carbocyclyl”). 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”). In some embodiments, a carbocyclyl group has 4 to 6 ring carbon atoms (“C4-6carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 6 ring carbon atoms (“C5-6carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (“C5-10 carbocyclyl”). Exemplary C3-6 carbocyclyl groups include cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), 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 (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), 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 (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenyl (C9), 13 / 156 13813260decahydronaphthalenyl (C10), spiro[4.5]decanyl (C10), and the like. Exemplary C3-8carbocyclyl 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 (C14), and the like. As the foregoing examples illustrate, in certain embodiments, 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. Unless otherwise specified, each instance of a carbocyclyl group is independently unsubstituted (an “unsubstituted carbocyclyl”) or substituted (a “substituted carbocyclyl”) with one or more substituents. In certain embodiments, the carbocyclyl group is an unsubstituted C3-14carbocyclyl. In certain embodiments, the carbocyclyl group is a substituted C3-14 carbocyclyl.

[0049] In some embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 14 ring carbon atoms (“C3-14cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 10 ring carbon atoms (“C3-10 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms (“C3-8 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms (“C3-6cycloalkyl”). In some embodiments, 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 (“C5-10cycloalkyl”). Examples of C5-6cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). Examples of C3-6cycloalkyl groups include the aforementioned C5-6 cycloalkyl groups as well as cyclopropyl (C3) and cyclobutyl (C4). Examples of C3-8cycloalkyl groups include the aforementioned C3-6cycloalkyl groups as well as cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified, each instance of a cycloalkyl group is independently unsubstituted (an “unsubstituted cycloalkyl”) or substituted (a “substituted cycloalkyl”) with one or more substituents. In certain embodiments, the cycloalkyl group is an unsubstituted C3-14cycloalkyl. In certain embodiments, the cycloalkyl group is a substituted C3-14 cycloalkyl. In certain embodiments, the carbocyclyl includes 0, 1, or 2 C=C double bonds in the carbocyclic ring system, as valency permits. 14 / 156 13813260

[0050] 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. In some embodiments, 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. In some embodiments, 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. Unless otherwise specified, each instance of heterocyclyl is independently unsubstituted (an “unsubstituted heterocyclyl”) or substituted (a “substituted heterocyclyl”) with one or more substituents. In certain embodiments, the heterocyclyl group is an unsubstituted 3–14 membered heterocyclyl. In certain embodiments, the heterocyclyl group is a substituted 3–14 membered heterocyclyl. In certain embodiments, 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.

[0051] In some embodiments, 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”). In some embodiments, 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”). In some embodiments, 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”). In some embodiments, the 5–6 membered heterocyclyl has 1–3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5–6 membered heterocyclyl has 1–2 ring heteroatoms 15 / 156 13813260selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5–6 membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0052] 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]diazepinyl, 1,4,5,7-tetrahydropyrano[3,4-b]pyrrolyl, 5,6-dihydro-4H-furo[3,2-b]pyrrolyl, 6,7-dihydro-5H- furo[3,2-b]pyranyl, 5,7-dihydro-4H-thieno[2,3-c]pyranyl, 2,3-dihydro-1H-pyrrolo[2,3- b]pyridinyl, 2,3-dihydrofuro[2,3-b]pyridinyl, 4,5,6,7-tetrahydro-1H-pyrrolo[2,3-b]pyridinyl, 4,5,6,7-tetrahydrofuro[3,2-c]pyridinyl, 4,5,6,7-tetrahydrothieno[3,2-b]pyridinyl, 1,2,3,4- tetrahydro-1,6-naphthyridinyl, and the like.

[0053] The term “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”). In some embodiments, an aryl group has 6 ring carbon atoms (“C6 aryl”; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms (“C10aryl”; e.g., naphthyl such as 1–naphthyl and 2-naphthyl). In some embodiments, an aryl group has 14 ring 16 / 156 13813260carbon atoms (“C14aryl”; 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. Unless otherwise specified, each instance of an aryl group is independently unsubstituted (an “unsubstituted aryl”) or substituted (a “substituted aryl”) with one or more substituents. In certain embodiments, the aryl group is an unsubstituted C6-14aryl. In certain embodiments, the aryl group is a substituted C6-14aryl.

[0054] The term “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”). In heteroaryl groups that contain one or more nitrogen atoms, in some embodiments the point of attachment is a carbon or nitrogen atom, as valency permits. In some embodiments, 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). In certain embodiments, 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. In certain embodiments, 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] In some embodiments, 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”). In some embodiments, 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”). In some embodiments, 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”). In some embodiments, the 5-6 membered heteroaryl has 1–3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, 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.

[0056] 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 13813260quinazolinyl. Exemplary tricyclic heteroaryl groups include phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl, and phenazinyl.

[0057] The term “unsaturated bond” refers to a double or triple bond.

[0058] 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.

[0060] Affixing the suffix “-ene” to a group indicates the group is a divalent moiety, e.g., 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, and heteroarylene is the divalent moiety of heteroaryl.

[0061] A group is optionally substituted unless expressly provided otherwise. The term “optionally substituted” refers to being substituted or unsubstituted. In certain embodiments, 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). In general, the term “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. Unless otherwise indicated, a “substituted” group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position. The term “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. For purposes of this disclosure, 19 / 156 13813260heteroatoms 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.

[0062] The term “acyl” refers to a group wherein the point of connectivity is a carbonyl (−C(=O)-). Non-limiting exemplary acyl groups include aldehydes (−C(=O)H), carboxylic acids (−C(=O)OH), ketones (-C(=O)R), acyl halides (-C(=O)(halogen)), esters (−C(=O)OR), and amides (−C(=O)NH2, −C(=O)NHR, −C(=O)NR2), wherein R is substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted heteroalkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0063] 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–), NO3–, ClO4–, 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 like), BF4−, PF4–, PF6–, AsF6–, SbF6–, B[3,5-(CF3)2C6H3]4]–, B(C6F5)4−, BPh4–, Al(OC(CF3)3)4–, and carborane anions (e.g., CB11H12–or (HCB11Me5Br6)–). Exemplary counterions which may be multivalent include CO32−, HPO42−, PO43−,B4O72−, SO42−, S2O32−, 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.

[0064] As used herein, the term “salt” refers to any and all salts, and encompasses pharmaceutically acceptable salts. 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. Examples of acid addition salts are salts of 20 / 156 13813260an 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. Other 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, persulfate, 3– phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, hippurate, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(C1–4 alkyl)4salts. 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.

[0065] The term “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. Other pharmaceutically acceptable 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 13813260lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3- phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. 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.

[0066] 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”. 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”.

[0067] 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.

[0068] It is also to be understood that 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”.

[0069] 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”. 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 13813260configuration 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”.

[0070] The terms “composition” and “formulation” are used interchangeably.

[0071] 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. In certain embodiments, 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)). In certain embodiments, 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. The term “patient” refers to a human subject in need of treatment of a disease.

[0072] The term “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.

[0073] The term “administer,” “administering,” or “administration” refers to implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing a compound described herein, or a composition thereof, in or on a subject.

[0074] The terms “treatment,” “treat,” and “treating” refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease described herein. In some embodiments, 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. For example, 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.

[0075] The terms “condition,” “disease,” and “disorder” are used interchangeably. 23 / 156 13813260

[0076] The terms “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 substances and tissues normally present in the body. In other words, the immune system mistakes some part of the body as a pathogen and attacks its own cells. 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.

[0077] The terms “neurological disease” and “neurological disorder” are used interchangeably herein and refer to any disease of the nervous system, including diseases that involve the central nervous system (brain, brainstem and cerebellum), the peripheral nervous system (including cranial nerves), and the autonomic nervous system (parts of which are located in both central and peripheral nervous system). 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. Examples of 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. Further examples of 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 13813260malformation; 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; blepharospasm; Bloch Sulzberger syndrome; brachial plexus injury; brain abscess; brain injury; brain tumors (including glioblastoma multiforme); spinal tumor; Brown-Sequard syndrome; Canavan disease; carpal tunnel syndrome (CTS); causalgia; central pain syndrome; central pontine myelinolysis; cephalic disorder; cerebral aneurysm; cerebral arteriosclerosis; cerebral atrophy; cerebral gigantism; cerebral palsy; Charcot-Marie-Tooth disease; chemotherapy-induced neuropathy and neuropathic pain; Chiari malformation; chorea; chronic inflammatory demyelinating polyneuropathy (CIDP); chronic pain; chronic regional pain syndrome; Coffin Lowry syndrome; coma, including persistent vegetative state; congenital facial diplegia; corticobasal degeneration; cranial arteritis; craniosynostosis; Creutzfeldt-Jakob disease; cumulative trauma disorders; Cushing’s syndrome; cytomegalic inclusion body disease (CIBD); cytomegalovirus infection; dancing eyes-dancing feet syndrome; Dandy-Walker syndrome; Dawson disease; De Morsier’s syndrome; Dejerine-Klumpke palsy; dementia; dermatomyositis; diabetic neuropathy; diffuse sclerosis; dysautonomia; dysgraphia; dyslexia; dystonias; early infantile epileptic encephalopathy; empty sella syndrome; encephalitis; encephaloceles; encephalotrigeminal angiomatosis; epilepsy; Erb’s palsy; essential tremor; Fabry’s disease; Fahr’s syndrome; fainting; familial spastic paralysis; febrile seizures; Fisher syndrome; Friedreich’s ataxia; frontotemporal dementia and other “tauopathies”; Gaucher’s disease; Gerstmann’s syndrome; giant cell arteritis; giant cell inclusion disease; globoid cell leukodystrophy; Guillain-Barre syndrome; HTLV-1 associated myelopathy; Hallervorden-Spatz disease; head injury; headache; hemifacial spasm; hereditary spastic paraplegia; heredopathia atactica polyneuritiformis; herpes zoster oticus; herpes zoster; Hirayama syndrome; HIV-associated dementia and neuropathy (see also neurological manifestations of AIDS); holoprosencephaly; Huntington’s disease and other polyglutamine repeat diseases; hydranencephaly; hydrocephalus; hypercortisolism; hypoxia; immune-mediated encephalomyelitis; inclusion body myositis; incontinentia pigmenti; infantile; phytanic acid storage disease; Infantile Refsum disease; infantile spasms; inflammatory myopathy; intracranial cyst; intracranial hypertension; Joubert syndrome; Kearns-Sayre syndrome; Kennedy disease; Kinsbourne syndrome; Klippel Feil syndrome; Krabbe disease; Kugelberg-Welander disease; kuru; Lafora disease; Lambert-Eaton myasthenic syndrome; Landau-Kleffner syndrome; lateral medullary (Wallenberg) syndrome; learning disabilities; Leigh’s disease; Lennox-Gastaut syndrome; 25 / 156 13813260Lesch-Nyhan syndrome; leukodystrophy; Lewy body dementia; lissencephaly; locked-in syndrome; Lou Gehrig’s disease (aka motor neuron disease or amyotrophic lateral sclerosis); lumbar disc disease; lyme disease-neurological sequelae; Machado-Joseph disease; macrencephaly; megalencephaly; Melkersson-Rosenthal syndrome; Menieres disease; meningitis; Menkes disease; metachromatic leukodystrophy; microcephaly; migraine; Miller Fisher syndrome; mini-strokes; mitochondrial myopathies; Mobius syndrome; monomelic amyotrophy; motor neurone disease; moyamoya disease; mucopolysaccharidoses; multi-infarct dementia; multifocal motor neuropathy; multiple sclerosis (e.g., relapsing remitting multiple sclerosis, primary progressive multiple sclerosis, or secondary progressive multiple sclerosis) and other demyelinating disorders; multiple system atrophy with postural hypotension; muscular dystrophy; myasthenia gravis; myelinoclastic diffuse sclerosis; myoclonic encephalopathy of infants; myoclonus; myopathy; myotonia congenital; narcolepsy; neurofibromatosis; neuroleptic malignant syndrome; neurological manifestations of AIDS; neurological sequelae of lupus; neuromyotonia; neuronal ceroid lipofuscinosis; neuronal migration disorders; Niemann-Pick disease; O’Sullivan-McLeod syndrome; occipital neuralgia; occult spinal dysraphism sequence; Ohtahara syndrome; olivopontocerebellar atrophy; opsoclonus myoclonus; optic neuritis; orthostatic hypotension; overuse syndrome; paresthesia; Parkinson’s disease; paramyotonia congenita; paraneoplastic diseases; paroxysmal attacks; Parry Romberg syndrome; Pelizaeus-Merzbacher disease; periodic paralyses; peripheral neuropathy; painful neuropathy and neuropathic pain; persistent vegetative state; pervasive developmental disorders; photic sneeze reflex; phytanic acid storage disease; Pick’s disease; pinched nerve; pituitary tumors; polymyositis; porencephaly; Post-Polio syndrome; postherpetic neuralgia (PHN); postinfectious encephalomyelitis; postural hypotension; Prader- Willi syndrome; primary lateral sclerosis; prion diseases; progressive; hemifacial atrophy; progressive multifocal leukoencephalopathy; progressive sclerosing poliodystrophy; progressive supranuclear palsy; pseudotumor cerebri; Ramsay-Hunt syndrome (Type I and Type II); Rasmussen’s Encephalitis; reflex sympathetic dystrophy syndrome; Refsum disease; repetitive motion disorders; repetitive stress injuries; restless legs syndrome; retrovirus- associated myelopathy; Rett syndrome; Reye’s syndrome; Saint Vitus Dance; Sandhoff disease; Schilder’s disease; schizencephaly; septo-optic dysplasia; shaken baby syndrome; shingles; Shy-Drager syndrome; Sjogren’s syndrome; sleep apnea; Soto’s syndrome; spasticity; spina bifida; spinal cord injury; spinal cord tumors; spinal muscular atrophy; stiff- person syndrome; stroke; Sturge-Weber syndrome; subacute sclerosing panencephalitis; subarachnoid hemorrhage; subcortical arteriosclerotic encephalopathy; sydenham chorea; 26 / 156 13813260syncope; syringomyelia; tardive dyskinesia; Tay-Sachs disease; temporal arteritis; tethered spinal cord syndrome; Thomsen disease; thoracic outlet syndrome; tic douloureux; Todd’s paralysis; Tourette syndrome; transient ischemic attack; transmissible spongiform encephalopathies; transverse myelitis; traumatic brain injury; tremor; trigeminal neuralgia; tropical spastic paraparesis; tuberous sclerosis; vascular dementia (multi-infarct dementia); vasculitis including temporal arteritis; Von Hippel-Lindau Disease (VHL); Wallenberg’s syndrome; Werdnig-Hoffman disease; West syndrome; whiplash; Williams syndrome; Wilson’s disease; and Zellweger syndrome.

[0078] The terms “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. The term “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, pernicious anemia, inflammatory dermatoses, usual interstitial pneumonitis (UIP), asbestosis, silicosis, bronchiectasis, berylliosis, talcosis, pneumoconiosis, 27 / 156 13813260sarcoidosis, desquamative interstitial pneumonia, lymphoid interstitial pneumonia, giant cell interstitial pneumonia, cellular interstitial pneumonia, extrinsic allergic alveolitis, Wegener’s granulomatosis and related forms of angiitis (temporal arteritis and polyarteritis nodosa), inflammatory dermatoses, hepatitis, delayed-type hypersensitivity reactions (e.g., poison ivy dermatitis), pneumonia, respiratory tract inflammation, Adult Respiratory Distress Syndrome (ARDS), encephalitis, immediate hypersensitivity reactions, asthma, hayfever, allergies, acute anaphylaxis, rheumatic fever, glomerulonephritis, pyelonephritis, cellulitis, cystitis, chronic cholecystitis, ischemia (ischemic injury), reperfusion injury, allograft rejection, host-versus- graft rejection, appendicitis, arteritis, blepharitis, bronchiolitis, bronchitis, cervicitis, cholangitis, chorioamnionitis, conjunctivitis, dacryoadenitis, dermatomyositis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, gingivitis, ileitis, iritis, laryngitis, myelitis, myocarditis, nephritis, omphalitis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, pharyngitis, pleuritis, phlebitis, pneumonitis, proctitis, prostatitis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, testitis, tonsillitis, urethritis, urocystitis, uveitis, vaginitis, vasculitis, vulvitis, vulvovaginitis, angitis, chronic bronchitis, osteomyelitis, optic neuritis, temporal arteritis, transverse myelitis, necrotizing fasciitis, and necrotizing enterocolitis. An ocular inflammatory disease includes, but is not limited to, post-surgical inflammation.

[0079] 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, diabetes (e.g., type I diabetes mellitus, Type II diabetes mellitus), a skin condition (e.g., psoriasis, eczema, burns, dermatitis, pruritus (itch)), endometriosis, Guillain-Barre syndrome, infection, ischemic heart disease, Kawasaki disease, glomerulonephritis, gingivitis, hypersensitivity, headaches (e.g., migraine headaches, tension headaches), ileus (e.g., postoperative ileus and ileus during sepsis), idiopathic thrombocytopenic purpura, interstitial cystitis (painful bladder syndrome), gastrointestinal disorder (e.g., selected from peptic ulcers, regional enteritis, diverticulitis, gastrointestinal bleeding, eosinophilic gastrointestinal disorders (e.g., eosinophilic esophagitis, eosinophilic gastritis, eosinophilic gastroenteritis, eosinophilic colitis), gastritis, diarrhea, 28 / 156 13813260gastroesophageal reflux disease (GORD, or its synonym GERD), inflammatory bowel disease (IBD) (e.g., Crohn’s disease, ulcerative colitis, collagenous colitis, lymphocytic colitis, ischemic colitis, diversion colitis, Behcet’s syndrome, indeterminate colitis) and inflammatory bowel syndrome (IBS)), lupus, multiple sclerosis, morphea, myasthenia gravis, myocardial ischemia, nephrotic syndrome, pemphigus vulgaris, pernicious anemia, peptic ulcers, polymyositis, primary biliary cirrhosis, neuroinflammation associated with brain disorders (e.g., Parkinson’s disease, Huntington’s disease, and Alzheimer’s disease), prostatitis, chronic inflammation associated with cranial radiation injury, pelvic inflammatory disease, reperfusion injury, regional enteritis, rheumatic fever, systemic lupus erythematosus, scleroderma, sarcoidosis, spondyloarthopathies, Sjogren’s syndrome, thyroiditis, transplantation rejection, tendonitis, trauma or injury (e.g., frostbite, chemical irritants, toxins, scarring, burns, physical injury), vasculitis, vitiligo and Wegener’s granulomatosis. In certain embodiments, the inflammatory disorder is selected from arthritis (e.g., rheumatoid arthritis), inflammatory bowel disease, inflammatory bowel syndrome, asthma, psoriasis, endometriosis, interstitial cystitis and prostatitis. In certain embodiments, the inflammatory condition is an acute inflammatory condition (e.g., for example, inflammation resulting from infection). In certain embodiments, 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.

[0080] The term “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); choriocarcinoma; chordoma; craniopharyngioma; colorectal cancer (e.g., colon cancer, rectal cancer, colorectal adenocarcinoma); connective tissue cancer; epithelial carcinoma; ependymoma; 29 / 156 13813260endotheliosarcoma (e.g., Kaposi’s sarcoma, multiple idiopathic hemorrhagic sarcoma); endometrial cancer (e.g., uterine cancer, uterine sarcoma); esophageal cancer (e.g., adenocarcinoma of the esophagus, Barrett’s adenocarcinoma); Ewing’s sarcoma; ocular cancer (e.g., intraocular melanoma, retinoblastoma); familiar hypereosinophilia; gall bladder cancer; gastric cancer (e.g., stomach adenocarcinoma); gastrointestinal stromal tumor (GIST); germ cell cancer; head and neck cancer (e.g., head and neck squamous cell carcinoma, oral cancer (e.g., oral squamous cell carcinoma), throat cancer (e.g., laryngeal cancer, pharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer)); hematopoietic cancers (e.g., leukemia such as acute lymphocytic leukemia (ALL) (e.g., B-cell ALL, T-cell ALL), acute myelocytic leukemia (AML) (e.g., B-cell AML, T-cell AML), chronic myelocytic leukemia (CML) (e.g., B-cell CML, T-cell CML), and chronic lymphocytic leukemia (CLL) (e.g., B-cell CLL, T-cell CLL)); lymphoma such as Hodgkin lymphoma (HL) (e.g., B-cell HL, T-cell HL) and non-Hodgkin lymphoma (NHL) (e.g., B-cell NHL such as diffuse large cell lymphoma (DLCL) (e.g., diffuse large B-cell lymphoma), follicular lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), mantle cell lymphoma (MCL), marginal zone B-cell lymphomas (e.g., mucosa-associated lymphoid tissue (MALT) lymphomas, nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma), primary mediastinal B-cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma (i.e., Waldenström’s macroglobulinemia), hairy cell leukemia (HCL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma and primary central nervous system (CNS) lymphoma; and T-cell NHL such as precursor T-lymphoblastic lymphoma / leukemia, peripheral T-cell lymphoma (PTCL) (e.g., cutaneous T-cell lymphoma (CTCL) (e.g., mycosis fungoides, Sezary syndrome), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathy type T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, and anaplastic large cell lymphoma); a mixture of one or more leukemia / lymphoma as described above; and multiple myeloma (MM)), heavy chain disease (e.g., alpha chain disease, gamma chain disease, mu chain disease); hemangioblastoma; hypopharynx cancer; inflammatory myofibroblastic tumors; immunocytic amyloidosis; kidney cancer (e.g., nephroblastoma a.k.a. 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. myelofibrosis 30 / 156 13813260(MF), chronic idiopathic myelofibrosis, chronic myelocytic leukemia (CML), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES)); neuroblastoma; neurofibroma (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 cancer (e.g., Paget’s disease of the penis and scrotum); pinealoma; primitive neuroectodermal tumor (PNT); plasma cell neoplasia; paraneoplastic syndromes; intraepithelial neoplasms; prostate cancer (e.g., prostate adenocarcinoma); rectal cancer; rhabdomyosarcoma; salivary gland cancer; skin cancer (e.g., squamous cell carcinoma (SCC), keratoacanthoma (KA), melanoma, basal cell carcinoma (BCC)); small bowel cancer (e.g., appendix cancer); soft tissue sarcoma (e.g., malignant fibrous histiocytoma (MFH), liposarcoma, malignant peripheral nerve sheath tumor (MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma); sebaceous gland carcinoma; small intestine cancer; sweat gland carcinoma; synovioma; testicular cancer (e.g., seminoma, testicular embryonal carcinoma); thyroid cancer (e.g., papillary carcinoma of the thyroid, papillary thyroid carcinoma (PTC), medullary thyroid cancer); urethral cancer; vaginal cancer; and vulvar cancer (e.g., Paget’s disease of the vulva).

[0081] The bicyclic moiety drawn herein as:meant to also encompass the following non-fully oxidized forms:. 31 / 156 13813260

[0082] The polycyclic moiety drawn herein as: , is meant to also encompass the following regioisomer:. Dendrimer Conjugates of Formulae (I′) and (I)

[0083] In one aspect, provided herein are dendrimer conjugates of Formula (I′):or a pharmaceutically acceptable salt thereof, wherein: D is a dendrimer; Z is substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted heteroalkylene, or substituted or unsubstituted heteroalkenylene; R1is 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; and p is an integer from 0-20, inclusive.

[0084] In some embodiments, the compound of Formula (I′) is of Formula (I) (e.g., the chelator is chelating a radionuclide).

[0085] In one aspect, provided herein are dendrimer conjugates of Formula (I):or a pharmaceutically acceptable salt thereof, wherein: D is a dendrimer; 32 / 156 13813260Z is substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted heteroalkylene, or substituted or unsubstituted heteroalkenylene; R1is 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; and p is an integer from 0-20, inclusive.

[0086] The term “dendrimer conjugate” refers to a dendrimer that comprises at least one agent, such as an active agent, imaging agent, or therapeutic agent described herein. In some embodiments, the dendrimer is conjugated to the at least one agent through a covalent or non- covalent linkage. In some embodiments, the dendrimer is conjugated to a chelator, which can chelate a radionuclide (i.e., an imaging agent). In some embodiments, the dendrimer is conjugated to the at least one agent through a chelator, such as a dendrimer conjugate of Formula (I), where R1is a chelator comprising a radionuclide. In some embodiments, 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. In some embodiments, terminal functional groups of a dendrimer include one or more hydroxyl groups, one or more amine groups, and / or one or more carboxyl groups. In some embodiments, the terminal functional groups of a dendrimer provide attachment sites through which the at least one agent is conjugated to form the dendrimer conjugate. In some embodiments, 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. In some embodiments of Formula (I′) or (I), D is a polyamidoamine (PAMAM), polypropylamine (POPAM), polyethylenimine, polylysine, polyester, iptycene, aliphatic poly(ether), or an aromatic polyether dendrimer. In some embodiments, D is a polyamidoamine (PAMAM) dendrimer. In some embodiments, D is a polypropylamine (POPAM) dendrimer. In some embodiments, D is a polyethylenimine dendrimer. In some embodiments, D is a polylysine dendrimer. In some embodiments, D is a polyester dendrimer. In some embodiments, D is an iptycene dendrimer. In some 33 / 156 13813260embodiments, 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.

[0089] In some embodiments of Formula (I′) or (I), D is a generation 4, generation 5, generation 6, generation 7, or generation 8 PAMAM dendrimer. In some embodiments, D is a generation 4 PAMAM dendrimer. In some embodiments, D is a generation 5 PAMAM dendrimer. In some embodiments, D is a generation 6 PAMAM dendrimer. In some embodiments, D is a generation 7 PAMAM dendrimer. In some embodiments, D is a generation 8 PAMAM dendrimer.

[0090] In some embodiments, 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. In some embodiments, D is a generation 6 PAMAM dendrimer, and m + n + p is 256.

[0091] In some embodiments of Formula (I′), R1is a radionuclide or a chelator of a radionuclide. In some embodiments, R1is a radionuclide. In some embodiments, R1is 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), R1is a radionuclide or a chelator comprising a radionuclide. In some embodiments, R1is a radionuclide. In some embodiments, R1is a chelator comprising a radionuclide.

[0093] In some embodiments of Formula (I′) or (I), the radionuclide is selected from the group consisting of18F,47Sc,51Cr,51Mn,52Fe,60Cu,62Cu,64Cu,67Cu,67Ga,68Ga,72As,76Br,77Br,88Y,89Zr,90Y,94mTc,99mTc,97Ru,103Ru,105Rh,109Pd,110In,111In ,117mSn,123I,124I,125I,131I,140La,141Ce,149Pm,153Sm,161Tb,165Dy,166Dy,166Ho,167Tm,168Yb,175Yb,177Lu,186Re,188Re,198Au,199Au,203Pb,211Bi,212Bi,213Bi,214Bi, and225Ac, or ion thereof. In some embodiments the radionuclide is18F,44Sc,47Sc,51Cr,51Mn,52Fe,55Co,60Cu,61Cu,62Cu,64Cu,67Cu,67Ga,68Ga,72As,76Br,77Br,82Rb,86Y,88Y,89Sr,89Zr,90Y,94mTc,99mTc,97Ru,103Ru, 34 / 156 13813260105Rh,109Pd,110In,111In ,117mSn,123I,124I,125I,131I,133Xe,140La,141Ce,149Pm,149Tb,152Tb,153Sm,161Tb,165Dy,166Dy,166Ho,167Tm,168Yb,175Yb,177Lu,186Re,188Re,198Au,199Au,201Tl,203Pb,211Bi,212Bi,212Pb,213Bi,214Bi,223Ra,225Ac, and227Th or ion thereof. In some embodiments, the radionuclide is18F,64Cu,90Y, or111In, or ion thereof. In some embodiments, the radionuclide is18F,64Cu,89Zr,90Y,111In,177Lu,203Pb, or225Ac, or ion thereof. In some embodiments, the radionuclide is18F,64Cu,90Y,111In,177Lu, or225Ac, or ion thereof. In some embodiments, the radionuclide is18F,64Cu, or177Lu, or ion thereof. In some embodiments, the radionuclide is11C,13N,18F,44Sc,51Cr,55Co,61Cu,64Cu,67Ga,67Cu,68Ga,82Rb,86Y,89Zr,89Sr,90Y,{99m}Tc,111In,{117m}Sn,123I,124I,125I,131I,133Xe,149Tb,152Tb,153Sm,161Tb,166Ho,166Ho,177Lu,186Re,188Re,201Tl,203Pb,212Pb,212Bi,213Bi,223Ra,225Ac, or227Th, or ion thereof. In some embodiments, the radionuclide is64Cu,90Y, or111In, or ion thereof. In some embodiments, the radionuclide is64Cu, or ion thereof. In some embodiments, the radionuclide is90Y, or ion thereof. In some embodiments, the radionuclide is111In, or ion thereof. In some embodiments, the radionuclide is18F, or ion thereof. In some embodiments, the radionuclide is89Zr, or ion thereof. In some embodiments, the radionuclide is90Y, or ion thereof. In some embodiments, the radionuclide is111In, or ion thereof. In some embodiments, the radionuclide is177Lu, or ion thereof. In some embodiments, the radionuclide is203Pb, or ion thereof. In some embodiments, the radionuclide is225Ac, or ion thereof. In some embodiments, D is a generation 4 PAMAM dendrimer, and wherein the radionuclide is18F, or ion thereof. In some embodiments, D is a generation 6 PAMAM dendrimer, and wherein the radionuclide is64Cu,90Y, or111In, or ion thereof.

[0094] In some embodiments of Formula (I′) or (I), R1is a radionuclide selected from the group consisting of18F,47Sc,51Cr,51Mn,52Fe,60Cu,62Cu,64Cu,67Cu,67Ga,68Ga,72As,76Br,77Br,88Y,89Zr,90Y,94mTc,99mTc,97Ru,103Ru,105Rh,109Pd,110In,111In ,117mSn,123I,124I,125I,131I,140La,141Ce,149Pm,153Sm,161Tb,165Dy,166Dy,166Ho,167Tm,168Yb,175Yb,177Lu,186Re,188Re,198Au,199Au,203Pb,211Bi,212Bi,213Bi,214Bi, and225Ac, or ion thereof. In some embodiments, the radionuclide is18F,64Cu,89Zr,90Y,111In,177Lu,203Pb, or225Ac, or ion thereof. In some embodiments, the R1is18F,44Sc,47Sc,51Cr,51Mn,52Fe,55Co,60Cu,61Cu,62Cu,64Cu,67Cu,67Ga,68Ga,72As,76Br,77Br,82Rb,86Y,88Y,89Sr,89Zr,90Y,94mTc,99mTc,97Ru,103Ru,105Rh,109Pd,110In,111In ,117mSn,123I,124I,125I,131I,133Xe,140La,141Ce,149Pm,149Tb,152Tb,153Sm,161Tb,165Dy,166Dy,166Ho,167Tm,168Yb,175Yb,177Lu,186Re,188Re,198Au,199Au,201Tl,203Pb,211Bi,212Bi,212Pb,213Bi,214Bi,223Ra,225Ac, and227Th or ion thereof. In some embodiments, R1is18F,64Cu,90Y,111In,177Lu, or225Ac, or ion thereof. In some embodiments, R1is18F,64Cu, or177Lu, or ion thereof. In some embodiments, R1is11C,13N,18F,44Sc,51Cr, 35 / 156 1381326055Co,61Cu,64Cu,67Ga,67Cu,68Ga,82Rb,86Y,89Zr,89Sr,90Y,{99m}Tc,111In,{117m}Sn,123I,124I,125I,131I,133Xe,149Tb,152Tb,153Sm,161Tb,166Ho,166Ho,177Lu,186Re,188Re,201Tl,203Pb,212Pb,212Bi,213Bi,223Ra,225Ac, or227Th, or ion thereof. In some embodiments, the radionuclide is64Cu,90Y, or111In, or ion thereof. In some embodiments, R1is18F,89Zr,90Y, or177Lu, or ion thereof. In some embodiments, R1is18F,64Cu,90Y, or111In, or ion thereof. In some embodiments, R1is64Cu,90Y, or111In, or ion thereof. In some embodiments, R1is64Cu, or ion thereof. In some embodiments, R1is90Y, or ion thereof. In some embodiments, R1is111In, or ion thereof. In some embodiments, R1is18F, or ion thereof.

[0095] In some embodiments of Formula (I′), R1is a chelator of a radionuclide (i.e., it chelates a radionuclide, but the radionuclide is not present (e.g., DOTA without an ion)). In some embodiments of Formula (I), R1is a chelator comprising a radionuclide. The chelator may be bound to the radionuclide or unbound to the radionuclide. In some embodiments, the chelator is an acyclic chelator, a cyclic chelator, a cryptand, a crown ether, a porphyrin, or a cyclic or acyclic polyphosphonate. In certain embodiments, the chelator is consisting of linear chelators, macrocyclic chelators, terpyridine chelators, N3S chelators, N2S2chelators, and N4chelators. In some embodiments, R1is DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10- tetraacetic acid), DOTMA (1R,4R,7R,10R)-α, α′, α″, α′″-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-(4,7,10-tris(2- amino-2-oxoethyl)-1,4,7,10-tetraazacyclododecan-1-yl)acetic acid), DOTA-GA anhydride (2,2′,2″-(10-(2,6-dioxotetrahydro-2H-pyran-3-yl)-1,4,7,10-tetraazacyclododecane-1,4,7- triyl)triacetic acid, DOTP (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetra(methylene phosphonic acid)), DOTMP (1,4,6,10-tetraazacyclodecane-1,4,7,10-tetramethylene phosphonic acid, DOTA-4AMP (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrakis(acetamido- methylenephosphonic acid), CB-TE2A (1,4,8,11-tetraazabicyclo[6.6.2]hexadecane-4,11- diacetic acid), NOTA (1,4,7-triazacyclononane-1,4,7-triacetic acid), NOTP (1,4,7- triazacyclononane-1,4,7-tri(methylene phosphonic acid), TETPA (1,4,8,11- tetraazacyclotetradecane-1,4,8,11-tetrapropionic acid), TETA (1,4,8,11- tetraazacyclotetradecane-1,4,8,11-tetra acetic acid), HEHA (1,4,7,10,13,16- hexaazacyclohexadecane-1,4,7,10,13,16-hexaacetic acid), PEPA (1,4,7,10,13- pentaazacyclopentadecane-N,N′,N″,N′″, N″″-pentaacetic acid), H4Octapa (N,N′-bis(6- carboxy-2-pyridylmethyl)-ethylenediamine-N,N′-diacetic acid), H2Dedpa (1,2-[[6-(carboxy)- pyridin-2-yl]-methylamino]ethane), H6phospa (N,N′-(methylenephosphonate)-N,N′-[6- 36 / 156 13813260(methoxycarbonyl)pyridin-2-yl]-methyl-1,2-diaminoethane), TTHA (triethylenetetramine- N,N,N′,N″,N′″, N″″-hexaacetic acid), DO2P (tetraazacyclododecane dimethanephosphonic acid), HP-DO3A (hydroxypropyltetraazacyclododecanetriacetic acid), EDTA (ethylenediaminetetraacetic acid), Deferoxamine, DTPA (diethylenetriaminepentaacetic acid), DTPA-BMA (diethylenetriaminepentaacetic acid-bismethylamide), HOPO (octadentate hydroxypyridinones), NODAGA (2-(4,7-bis(carboxymethyl)-1,4,7-triazonan-1-yl)pentanedioic acid), MACROPA (6-((16-((6-Carboxypyridin-2-yl)methyl)-1,4,10,13-tetraoxa-7,16- diazacyclooctadecan-7-yl)methyl)-4-isothiocyanatopicolinic acid), or porphyrin. In some embodiments, 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), monoamidemonoaminedithiols, and diaminedithiols. In certain embodiments, 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). In some embodiments, the chelator is DOTA. In some embodiments, R1is DOTA chelated to111In. In some embodiments, R1is DOTA chelated to111In3+. In some embodiments, R1is DOTA chelated to177Lu. In some embodiments, R1is DOTA chelated to177Lu3+. In some embodiments, R1is DOTA chelated to90Y. In some embodiments, R1is DOTA chelated to90Y3+. In some embodiments, the chelator is NOTA. In some embodiments, R1is NOTA chelated to64Cu. In some embodiments, R1is NOTA chelated to64Cu2+. In some embodiments, R1is NOTA chelated to177Lu. In some embodiments, R1is NOTA chelated to177Lu3+. In some embodiments, R1is NOTA chelated to177Lu2+. In some embodiments, R1is NOTA chelated to111In. In some embodiments, R1is NOTA chelated to111In3+. In some embodiments, R1is NOTA chelated to90Y. In some embodiments, R1is NOTA chelated to90Y3+. In some embodiments, the chelator is NODAGA. In some embodiments, R1is NODAGA chelated to177Lu. In some embodiments, R1is NODAGA chelated to177Lu3+. In some embodiments, R1is NODAGA chelated to177Lu2+. In some embodiments, R1is NODAGA chelated to64Cu. In some embodiments, R1is NODAGA chelated to64Cu2+. In some embodiments, R1is NODAGA chelated to111In. In some embodiments, R1is NODAGA chelated to111In3+. In 37 / 156 13813260some embodiments, R1is NODAGA chelated to90Y. In some embodiments, R1is NODAGA chelated to90Y3+. In some embodiments, the chelator is MACROPA. In some embodiments, R1is MACROPA chelated to177Lu. In some embodiments, R1is MACROPA chelated to177Lu3+. In some embodiments, R1is MACROPA chelated to177Lu2+. In some embodiments, R1is MACROPA chelated to64Cu. In some embodiments, R1is MACROPA chelated to64Cu2+. In some embodiments, R1is MACROPA chelated to111In. In some embodiments, R1is MACROPA chelated to111In3+. In some embodiments, R1is MACROPA chelated to90Y. In some embodiments, R1is MACROPA chelated to90Y3+. In some embodiments, R1is MACROPA chelated to225Ac. In some embodiments, R1is MACROPA chelated to225Ac3+. In some embodiments, the chelator is MACROPA. In some embodiments, R1is 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. In some embodiments, 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. In some embodiments, the chelator and / or R1is as in Figure 29B. In some embodiments, R1is38 / 156 1381326039 / 156 13813260some embodiments, certain embodiments, R1is.

[0097] In some embodiments of Formula (I′) or (I), Z is substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, or substituted or unsubstituted heteroalkylene, or 40 / 156 13813260substituted or unsubstituted heteroalkenylene. In certain embodiments, Z is substituted or unsubstituted alkylene. In some embodiments, Z is substituted or unsubstituted C1-C6 alkylene. In certain embodiments, Z is substituted or unsubstituted propylene. In some embodiments, Z.

[0098] In some embodiments of Formula (I′) or (I), 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.

[0099] In some embodiments of Formula (I′) or (I), m is an integer from 16-4095, inclusive. In certain embodiments, m is an integer from 52-56, inclusive. In some embodiments, m is 54.

[0100] In some embodiments of Formula (I′) or (I), 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. In some embodiments, n is 12.

[0101] 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. In some embodiments, p is 10. In certain embodiments, p is 11. In some embodiments, p is 12.

[0102] 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. In some embodiments, 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 13813260embodiments, 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.

[0103] 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.

[0104] In some embodiments, the dendrimer conjugate of Formula (I′) or (I) is of the formula:, or a pharmaceutically acceptable salt thereof.

[0105] In some embodiments, the dendrimer conjugate of Formula (I′) or (I) is of the formula:, or a pharmaceutically acceptable salt thereof.

[0106] In some embodiments, the dendrimer conjugate of Formula (I′) or (I) is of the formula:, or a pharmaceutically acceptable salt thereof. In some embodiments, 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.

[0107] In some embodiments, the dendrimer conjugate of Formula (I′) or (I) is of the formula: 42 / 156 13813260, or a pharmaceutically acceptable salt thereof. In some embodiments, 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.

[0108] 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. 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.

[0109] In some embodiments, the dendrimer conjugate of Formula (I′) or (I) is of the formula:, or a pharmaceutically acceptable salt thereof. In some embodiments, 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.

[0110] In some embodiments, 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, 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, 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. In some embodiments, the dendrimer conjugate of Formula (I′) or (I) is in the form of a dendrimer conjugate. Dendrimer Conjugates of Formulae (II′) and (II)

[0111] In another aspect provided herein are dendrimer conjugates of Formula (II′):or a pharmaceutically acceptable salt thereof, wherein: D is a dendrimer; R1is a radionuclide or a chelator of a radionuclide; RAis a reactive moiety comprising a cyclic alkene or cyclic alkyne; RBis a polycyclic moiety; L1and L2are 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.

[0112] In some embodiments, the compound of Formula (II′) is of Formula (II) (e.g., the chelator is chelating a radionuclide). Thus, in some embodiments, 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.

[0113] In another aspect provided herein are dendrimer conjugates of Formula (II):or a pharmaceutically acceptable salt thereof, wherein: D is a dendrimer; R1is a radionuclide or a chelator comprising a radionuclide; RAis a reactive moiety comprising a cyclic alkene or cyclic alkyne; RBis a polycyclic moiety; L1and L2are 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.

[0114] The term “dendrimer conjugate” refers to a dendrimer that comprises at least one agent, such as an active agent, imaging agent, or therapeutic agent described herein. In some embodiments, the dendrimer is conjugated to the at least one agent through a covalent or non- covalent linkage. In some embodiments, the dendrimer is conjugated to a chelator, which can chelate a radionuclide (i.e., an imaging agent). In some embodiments, the dendrimer is conjugated to the at least one agent through a chelator, such as a dendrimer conjugate of Formula (II), where R1is a chelator comprising a radionuclide. In some embodiments, 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. In some embodiments, terminal functional groups of a dendrimer include one or more hydroxyl groups, one or more amine groups, and / or one or more carboxyl groups. In some embodiments, the terminal functional groups of a dendrimer provide attachment sites through which the at least one agent is conjugated to form the dendrimer conjugate. In some embodiments, 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 13813260dendrimer 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.

[0115] D is a dendrimer as described herein. In some embodiments of Formula (II′) or (II), D is a polyamidoamine (PAMAM), polypropylamine (POPAM), polyethylenimine, polylysine, polyester, iptycene, aliphatic poly(ether), or an aromatic polyether dendrimer. In some embodiments, D is a polyamidoamine (PAMAM) dendrimer. In some embodiments, D is a polypropylamine (POPAM) dendrimer. In some embodiments, D is a polyethylenimine dendrimer. In some embodiments, D is a polylysine dendrimer. In some embodiments, D is a polyester dendrimer. In some embodiments, D is an iptycene dendrimer. In some embodiments, D is an aliphatic poly(ether) dendrimer. In some embodiments, D is an aromatic polyether dendrimer.

[0116] 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.

[0117] In some embodiments of Formula (II′) or (II), D is a generation 4, generation 5, generation 6, generation 7, or generation 8 PAMAM dendrimer. In some embodiments, D is a generation 4 PAMAM dendrimer. In some embodiments, D is a generation 5 PAMAM dendrimer. In some embodiments, D is a generation 6 PAMAM dendrimer. In some embodiments, D is a generation 7 PAMAM dendrimer. In some embodiments, D is a generation 8 PAMAM dendrimer.

[0118] In some embodiments, 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. In some embodiments, D is a generation 6 PAMAM dendrimer, and m + n + p is 256.

[0119] In some embodiments of Formula (II′), R1is a radionuclide or a chelator of a radionuclide. In some embodiments, R1is a radionuclide. In some embodiments, R1is a chelator of a radionuclide (i.e., a chelator such as DOTA without the radionuclide present, but will chelate the radionuclide). 46 / 156 13813260

[0120] In some embodiments of Formula (II), R1is a radionuclide or a chelator comprising a radionuclide. In some embodiments, R1is a radionuclide. In some embodiments, R1is a chelator comprising a radionuclide.

[0121] In some embodiments of Formula (II′) or (II), the radionuclide is selected from the group consisting of18F,47Sc,51Cr,51Mn,52Fe,60Cu,62Cu,64Cu,67Cu,67Ga,68Ga,72As,76Br,77Br,88Y,89Zr,90Y,94mTc,99mTc,97Ru,103Ru,105Rh,109Pd,110In,111In ,117mSn,123I,124I,125I,embodiments, the radionuclide is18F,64Cu,90Y, or111In, or ion thereof. In some embodiments, the radionuclide is18F,64Cu,89Zr,90Y,111In,177Lu,203Pb, or225Ac, or ion thereof. In some embodiments, the radionuclide is18F,64Cu,90Y,111In,177Lu, or225Ac, or ion thereof. In some embodiments, the radionuclide is18F,64Cu, or177Lu, or ion thereof. In some embodiments, the radionuclide is11C,13N,18F,44Sc,51Cr,55Co,61Cu,64Cu,67Ga,67Cu,68Ga,82Rb,86Y,89Zr,89Sr,90Y,{99m}Tc,111In,{117m}Sn,123I,124I,125I,131I,133Xe,149Tb,152Tb,153Sm,161Tb,166Ho,166Ho,177Lu,186Re,188Re,201Tl,203Pb,212Pb,212Bi,213Bi,223Ra,225Ac, or227Th, or ion thereof. In some embodiments, the radionuclide is64Cu,90Y, or111In, or ion thereof. In some embodiments, the radionuclide is64Cu, or ion thereof. In some embodiments, the radionuclide is90Y, or ion thereof. In some embodiments, the radionuclide is111In, or ion thereof. In some embodiments, the radionuclide is18F, or ion thereof. In some embodiments, the radionuclide is89Zr, or ion thereof. In some embodiments, the radionuclide is90Y, or ion thereof. In some embodiments, the radionuclide is111In, or ion thereof. In some embodiments, the radionuclide is177Lu, or ion thereof. In some embodiments, the radionuclide is203Pb, or ion thereof. In some embodiments, the radionuclide is225Ac, or ion thereof. In some embodiments, D is a generation 4 PAMAM dendrimer, and wherein the radionuclide is18F, or ion thereof. In some embodiments, D is a generation 6 PAMAM dendrimer, and wherein the radionuclide is64Cu,90Y, or111In, or ion thereof.

[0122] In some embodiments of Formula (II′) or (II), R1is a radionuclide selected from the group consisting of18F,47Sc,51Cr,51Mn,52Fe,60Cu,62Cu,64Cu,67Cu,67Ga,68Ga,72As,76Br,77Br,88Y,89Zr,90Y,94mTc,99mTc,97Ru,103Ru,105Rh,109Pd,110In,111In ,117mSn,123I,124I,125I, 47 / 156 13813260131I,140La,141Ce,149Pm,153Sm,161Tb,165Dy,166Dy,166Ho,167Tm,168Yb,175Yb,177Lu,186Re,188Re,198Au,199Au,203Pb,211Bi,212Bi,213Bi,214Bi, and225Ac, or ion thereof. In some embodiments, the radionuclide is18F,64Cu,89Zr,90Y,111In,177Lu,203Pb, or225Ac, or ion thereof. In some embodiments, the R1is18F,44Sc,47Sc,51Cr,51Mn,52Fe,55Co,60Cu,61Cu,62Cu,64Cu,67Cu,67Ga,68Ga,72As,76Br,77Br,82Rb,86Y,88Y,89Sr,89Zr,90Y,94mTc,99mTc,97Ru,103Ru,105Rh,109Pd,110In,111In ,117mSn,123I,124I,125I,131I,133Xe,140La,141Ce,149Pm,149Tb, 188Re,198Au,199Au,ion thereof. In some embodiments, R1is18F,64Cu,90Y,111In,177Lu, or225Ac, or ion thereof. In some embodiments,embodiments, R1is18F,64Cu, or177Lu, or ion thereof. In some embodiments, R1is11C,13N,18F,44Sc,51Cr,55Co,61Cu,64Cu,67Ga,67Cu,68Ga,82Rb,86Y,89Zr,89Sr,90Y,{99m}Tc,111In,{117m}Sn,123I,124I,125I,131I,133Xe,149Tb,152Tb,153Sm,161Tb,166Ho,166Ho,177Lu,186Re,188Re,201Tl,203Pb,212Pb,212Bi,213Bi,223Ra,225Ac, or227Th, or ion thereof. In some embodiments, the radionuclide is64Cu,90Y, or111In, or ion thereof. In some embodiments, R1is18F,89Zr,90Y, or177Lu, or ion thereof. In some embodiments, R1is18F,64Cu,90Y, or111In, or ion thereof. In some embodiments, R1is64Cu,90Y, or111In, or ion thereof. In some embodiments, R1is64Cu, or ion thereof. In some embodiments, R1is90Y, or ion thereof. In some embodiments, R1is111In, or ion thereof. In some embodiments, R1is18F, or ion thereof.

[0123] In some embodiments of Formula (II′), R1is a chelator of a radionuclide (i.e., it chelates a radionuclide, but the radionuclide is not present (e.g., DOTA without an ion)). In some embodiments of Formula (II), R1is a chelator comprising a radionuclide. The chelator may be bound to the radionuclide, or unbound to the radionuclide. In some embodiments, the chelator is an acyclic chelator, a cyclic chelator, a cryptand, a crown ether, a porphyrin, or a cyclic or acyclic polyphosphonate. In certain embodiments, the chelator is consisting of linear chelators, macrocyclic chelators, terpyridine chelators, N3S chelators, N2S2 chelators, and N4 chelators. In some embodiments, R1is DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10- tetraacetic acid), DOTMA (1R,4R,7R,10R)-α, α′, α″, α′″-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-(4,7,10-tris(2- amino-2-oxoethyl)-1,4,7,10-tetraazacyclododecan-1-yl)acetic acid), DOTA-GA anhydride (2,2′,2″-(10-(2,6-dioxotetrahydro-2H-pyran-3-yl)-1,4,7,10-tetraazacyclododecane-1,4,7- triyl)triacetic acid, DOTP (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetra(methylene 48 / 156 13813260phosphonic acid)), DOTMP (1,4,6,10-tetraazacyclodecane-1,4,7,10-tetramethylene phosphonic acid, DOTA-4AMP (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrakis(acetamido- methylenephosphonic acid), CB-TE2A (1,4,8,11-tetraazabicyclo[6.6.2]hexadecane-4,11- diacetic acid), NOTA (1,4,7-triazacyclononane-1,4,7-triacetic acid), NOTP (1,4,7- triazacyclononane-1,4,7-tri(methylene phosphonic acid), TETPA (1,4,8,11- tetraazacyclotetradecane-1,4,8,11-tetrapropionic acid), TETA (1,4,8,11- tetraazacyclotetradecane-1,4,8,11-tetra acetic acid), HEHA (1,4,7,10,13,16- hexaazacyclohexadecane-1,4,7,10,13,16-hexaacetic acid), PEPA (1,4,7,10,13- pentaazacyclopentadecane-N,N′,N″,N′″, N″″-pentaacetic acid), H4Octapa (N,N′-bis(6- carboxy-2-pyridylmethyl)-ethylenediamine-N,N′-diacetic acid), H2Dedpa (1,2-[[6-(carboxy)- pyridin-2-yl]-methylamino]ethane), H6phospa (N,N′-(methylenephosphonate)-N,N′-[6- (methoxycarbonyl)pyridin-2-yl]-methyl-1,2-diaminoethane), TTHA (triethylenetetramine- N,N,N′,N″,N′″, N″″-hexaacetic acid), DO2P (tetraazacyclododecane dimethanephosphonic acid), HP-DO3A (hydroxypropyltetraazacyclododecanetriacetic acid), EDTA (ethylenediaminetetraacetic acid), Deferoxamine, DTPA (diethylenetriaminepentaacetic acid), DTPA-BMA (diethylenetriaminepentaacetic acid-bismethylamide), HOPO (octadentate hydroxypyridinones), NODAGA (2-(4,7-bis(carboxymethyl)-1,4,7-triazonan-1-yl)pentanedioic acid), MACROPA (6-((16-((6-Carboxypyridin-2-yl)methyl)-1,4,10,13-tetraoxa-7,16- diazacyclooctadecan-7-yl)methyl)-4-isothiocyanatopicolinic acid), or porphyrin. In some embodiments, 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), monoamidemonoaminedithiols, and diaminedithiols. In certain embodiments, 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). In some embodiments, the chelator is DOTA. In some embodiments, R1is DOTA chelated to111In. In some embodiments, R1is DOTA chelated to111In3+. In some embodiments, R1is DOTA chelated to177Lu. In some embodiments, R1is DOTA chelated to177Lu3+. In some embodiments, R1is DOTA chelated to90Y. In some embodiments, R1is DOTA chelated to90Y3+. In some 49 / 156 13813260embodiments, the chelator is NOTA. In some embodiments, R1is NOTA chelated to64Cu. In some embodiments, R1is NOTA chelated to64Cu2+. In some embodiments, R1is NOTA chelated to177Lu. In some embodiments, R1is NOTA chelated to177Lu3+. In some embodiments, R1is NOTA chelated to177Lu2+. In some embodiments, R1is NOTA chelated to111In. In some embodiments, R1is NOTA chelated to111In3+. In some embodiments, R1is NOTA chelated to90Y. In some embodiments, R1is NOTA chelated to90Y3+. In some embodiments, the chelator is NODAGA. In some embodiments, R1is NODAGA chelated to177Lu. In some embodiments, R1is NODAGA chelated to177Lu3+. In some embodiments, R1is NODAGA chelated to177Lu2+. In some embodiments, R1is NODAGA chelated to64Cu. In some embodiments, R1is NODAGA chelated to64Cu2+. In some embodiments, R1is NODAGA chelated to111In. In some embodiments, R1is NODAGA chelated to111In3+. In some embodiments, R1is NODAGA chelated to90Y. In some embodiments, R1is NODAGA chelated to90Y3+. In some embodiments, the chelator is MACROPA. In some embodiments, R1is MACROPA chelated to177Lu. In some embodiments, R1is MACROPA chelated to177Lu3+. In some embodiments, R1is MACROPA chelated to177Lu2+. In some embodiments, R1is MACROPA chelated to64Cu. In some embodiments, R1is MACROPA chelated to64Cu2+. In some embodiments, R1is MACROPA chelated to111In. In some embodiments, R1is MACROPA chelated to111In3+. In some embodiments, R1is MACROPA chelated to90Y. In some embodiments, R1is MACROPA chelated to90Y3+. In some embodiments, R1is MACROPA chelated to225Ac. In some embodiments, R1is MACROPA chelated to225Ac3+. In some embodiments, the chelator is MACROPA. In some embodiments, R1is 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. In some embodiments, 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. In some embodiments, the chelator and / or R1is as in Figure 29B. In some embodiments, R1is50 / 156 1381326051 / 156 13813260

[0124] As provided herein, RAis a reactive moiety comprising a cyclic alkene or cyclic alkyne. In some embodiments, RAis cyclooctene. In some embodiments, RAis:52 / 156 13813260some embodiments, RAis: . In some embodiments, RAis dibenzocyclooctyne. Insome embodiments, RA is dibenzoazocyne. In some embodiments,.certain embodiments,

[0125] As provided herein, RBis a polycyclic moiety. In some embodiments, RBis a polycyclic moiety resulting from cycloaddition reaction of the cyclic alkene or cyclic alkyne of RA. In some embodiments, RBis a polycyclic moiety resulting from cycloaddition reaction of cyclooctene. In some embodiments, RBis a polycyclic moiety resulting from cycloaddition reaction of cyclooctene with substituted or unsubstituted tetrazine. In some embodiments, RBis a polycyclic moiety resulting from cycloaddition reaction of dibenzoazocyne. In some embodiments, RBis a polycyclic moiety resulting from cycloaddition reaction of dibenzoazocyne with substituted or unsubstituted azide. In some embodiments, RBis. 53 / 156 13813260

[0127] As provided herein, L1and L2are each independently a linker. In some embodiments, L1and L2are 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. In some embodiments, L1is 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. In some embodiments, L2is 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.

[0128] In certain embodiments, L1comprises one or more groups selected from -O- and - NHC(=O)-. In certain embodiments, L1comprises one or more groups selected from (-CH2-O- CH2-), -O-, and -NHC(=O)-. In certain embodiments, L1is substituted or unsubstituted 54 / 156 13813260alkylene wherein one or more backbone carbon atoms have been replaced one or more groups independently selected from -O- and -NHC(=O)-. In certain embodiments, L1is substituted or unsubstituted alkylene wherein one or more backbone carbon atoms have been replaced with one or more groups independently selected from (-CH2-O-CH2-), -O-, and -NHC(=O)-. In some embodiments,some embodiments, L1.

[0129] In certain embodiments, L2comprises one or more groups selected from -O- and -NH- . In some embodiments, L2comprises one or more groups selected from (-CH2-O-CH2-), -O-, - NH-, and -arylene-. In certain embodiments, L2is substituted or unsubstituted alkylene wherein one or more backbone carbon atoms have been replaced with one or more groups independently selected from (-CH2-O-CH2-) and -NH-. In certain embodiments, L2is 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, L2is substituted or unsubstituted alkylene wherein one or more backbone carbon atoms have been replaced with one or more groups independently selected from - 55 / 156 13813260arylene- and -NH-. In some embodiments, L2is . In some embodiments, L2is.

[0130] In some embodiments of Formula (II′) or (II), 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.

[0131] In some embodiments of Formula (II′) or (II), n is an integer from 1-20, inclusive. In some embodiments, 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.

[0132] In some embodiments of Formula (II′) or (II), 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. In certain embodiments, p is 11. In some embodiments, p is 12.

[0133] 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 13813260inclusive. 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. In some embodiments, 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.

[0134] 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.

[0135] In some embodiments of Formula (II′) or (II), m, n, p, and D are as defined below. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In certain embodiments, 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. In some embodiments, m is an integer from 200- 300, inclusive; n is an integer from 3-7, inclusive; p is an integer from 0-7, 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 0-16, inclusive; and D is a generation 6 PAMAM dendrimer. In some embodiments, 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. In certain embodiments, m is 251; p is 5; n is 5; and D is a generation 6 PAMAM dendrimer. In certain embodiments, m is 251; p is 0; n is 5; and D is a generation 6 PAMAM dendrimer.

[0136] In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In certain embodiments, m is 60; p is an integer from 0-5, inclusive; n is an integer from 2-6, inclusive; 57 / 156 13813260and 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. In some embodiments, 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.

[0137] In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In certain embodiments, 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. In some embodiments, m is an integer from 200- 300, inclusive; n is an integer from 3-7, inclusive; p is an integer from 0-3, 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 0-3, inclusive; and D is a generation 6 PAMAM dendrimer. In some embodiments, 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.

[0138] In some embodiments, the dendrimer conjugate of Formula (II′) or (II) is of the formula:, or a pharmaceutically acceptable salt thereof.

[0139] In some embodiments, the dendrimer conjugate of Formula (II′) or (II) is of the formula: 58 / 156 13813260, or a pharmaceutically acceptable salt thereof.

[0140] In some embodiments, the dendrimer conjugate of Formula (II′) or (II) is of the formula:, or a pharmaceutically acceptable salt thereof.

[0141] In some embodiments, the dendrimer conjugate of Formula (II′) or (II) is of the formula:, or a pharmaceutically acceptable salt thereof.

[0142] In some embodiments, the dendrimer conjugate of Formula (II′) or (II) is of the formula:, or a pharmaceutically acceptable salt thereof. 59 / 156 13813260

[0143] In some embodiments, the dendrimer conjugate of Formula (II′) or (II) is of the formula:, or a pharmaceutically acceptable salt thereof.

[0144] In some embodiments, the dendrimer conjugate of Formula (II′) or (II) is of the formula:, or a pharmaceutically acceptable salt thereof.

[0145] In some embodiments, the dendrimer conjugate of Formula (II′) or (II) is of the formula:, or a pharmaceutically acceptable salt thereof.

[0146] In some embodiments, the dendrimer conjugate of Formula (II′) or (II) is of the formula:, or a pharmaceutically acceptable salt thereof.

[0147] In some embodiments, the dendrimer conjugate of Formula (II′) or (II) is of the formula: 60 / 156 13813260, or a pharmaceutically acceptable salt thereof.

[0148] In some embodiments, the dendrimer conjugate of Formula (II′) or (II) is of the formula:, or a pharmaceutically acceptable salt thereof.

[0149] In some embodiments, the dendrimer conjugate of Formula (II′) or (II) is of the formula: dendrimer conjugate is of the formula:, or a pharmaceutically acceptable salt thereof.

[0150] In some embodiments, the dendrimer conjugate of Formula (II′) is of the formula:, or a pharmaceutically acceptable salt thereof.

[0151] In some embodiments, the dendrimer conjugate of Formula (II′) is of the formula: 61 / 156 13813260, or a pharmaceutically acceptable salt thereof.

[0152] In some embodiments, the dendrimer conjugate of Formula (II′) is of the formula:, or a pharmaceutically acceptable salt thereof.

[0153] In some embodiments, the dendrimer conjugate of Formula (II′) is of the formula:, or a pharmaceutically acceptable salt thereof.

[0154] In some embodiments, the dendrimer conjugate of Formula (II′) is of the formula:, or a pharmaceutically acceptable salt thereof.

[0155] In some embodiments, the dendrimer conjugate of Formula (II′) is of the formula: 62 / 156 13813260, or a pharmaceutically acceptable salt thereof.

[0156] In some embodiments, the dendrimer conjugate of Formula (II′) is of the formula:, or a pharmaceutically acceptable salt thereof.

[0157] In some embodiments, the dendrimer conjugate of Formula (II′) is of the formula:, or a pharmaceutically acceptable salt thereof.

[0158] In some embodiments, the dendrimer conjugate of Formula (II′) is of the formula:, or a pharmaceutically acceptable salt thereof.

[0159] In some embodiments, the dendrimer conjugate of Formula (II′) is of the formula: 63 / 156 13813260, or a pharmaceutically acceptable salt thereof.

[0160] In some embodiments, the dendrimer conjugate of Formula (II′) is of the formula:, or a pharmaceutically acceptable salt thereof.

[0161] In some embodiments, the dendrimer conjugate of Formula (II′) is of the formula:, or a pharmaceutically acceptable salt thereof.

[0162] In some embodiments, the dendrimer conjugate of Formula (II′) is of the formula:, or a pharmaceutically acceptable salt thereof.

[0163] In some embodiments, the dendrimer conjugate of Formula (II′) is of the formula: 64 / 156 13813260, or a pharmaceutically acceptable salt thereof.

[0164] In some embodiments, the dendrimer conjugate of Formula (II′) is of the formula:, or a pharmaceutically acceptable salt thereof.

[0165] In some embodiments, the dendrimer conjugate of Formula (II′) is of the formula:, or a pharmaceutically acceptable salt thereof.

[0166] In some embodiments, the dendrimer conjugate of Formula (II′) is of the formula:, or a pharmaceutically acceptable salt thereof.

[0167] In some embodiments, the dendrimer conjugate of Formula (II′) is of the formula: 65 / 156 13813260, or a pharmaceutically acceptable salt thereof.

[0168] In some embodiments, the dendrimer conjugate of Formula (II′) is of the formula:, or a pharmaceutically acceptable salt thereof.

[0169] In some embodiments, the dendrimer conjugate of Formula (II′) is of the formula:, or a pharmaceutically acceptable salt thereof.

[0170] In some embodiments, the dendrimer conjugate of Formula (II′) is of the formula:, or a pharmaceutically acceptable salt thereof.

[0171] In some embodiments, the dendrimer conjugate of Formula (II′) is of the formula: 66 / 156 13813260, or a pharmaceutically acceptable salt thereof.

[0172] In some embodiments, the dendrimer conjugate of Formula (II′) is of the formula:, or a pharmaceutically acceptable salt thereof.

[0173] In some embodiments, the dendrimer conjugate of Formula (II′) is of the formula:, or a pharmaceutically acceptable salt thereof.

[0174] In some embodiments, the dendrimer conjugate of Formula (II′) is of the formula:, or a pharmaceutically acceptable salt thereof.

[0175] In some embodiments, the dendrimer conjugate of Formula (II′) is of the formula: 67 / 156 13813260, or a pharmaceutically acceptable salt thereof.

[0176] In some embodiments, the dendrimer conjugate of Formula (II′) is of the formula:, or a pharmaceutically acceptable salt thereof.

[0177] In some embodiments, the dendrimer conjugate of Formula (II′) is of the formula:, or a pharmaceutically acceptable salt thereof.

[0178] In some embodiments, the dendrimer conjugate of Formula (II′) is of the formula:, or a pharmaceutically acceptable salt thereof.

[0179] In some embodiments, the dendrimer conjugate of Formula (II′) is of the formula: 68 / 156 13813260, or a pharmaceutically acceptable salt thereof.

[0180] In some embodiments, the dendrimer conjugate of Formula (II′) is of the formula:, or a pharmaceutically acceptable salt thereof.

[0181] In some embodiments, the dendrimer conjugate of Formula (II′) is of the formula: 69 / 156 13813260, or a pharmaceutically acceptable salt thereof.

[0182] In some embodiments, the dendrimer conjugate of Formula (II) is of the formula:, or a pharmaceutically acceptable salt thereof.

[0183] In some embodiments, the dendrimer conjugate of Formula (II) is of the formula:, or a pharmaceutically acceptable salt thereof.

[0184] In some embodiments, the dendrimer conjugate of Formula (II) is of the formula: 70 / 156 13813260, or a pharmaceutically acceptable salt thereof.

[0185] In some embodiments, the dendrimer conjugate of Formula (II) is of the formula:, or a pharmaceutically acceptable salt thereof.

[0186] In some embodiments, the dendrimer conjugate of Formula (II) is of the formula:, or a pharmaceutically acceptable salt thereof.

[0187] In some embodiments, the dendrimer conjugate of Formula (II) is of the formula:, or a pharmaceutically acceptable salt thereof.

[0188] In some embodiments, the dendrimer conjugate of Formula (II) is of the formula: 71 / 156 13813260, or a pharmaceutically acceptable salt thereof.

[0189] In some embodiments, the dendrimer conjugate of Formula (II) is of the formula:, or a pharmaceutically acceptable salt thereof.

[0190] In some embodiments, the dendrimer conjugate of Formula (II) is of the formula:, or a pharmaceutically acceptable salt thereof.

[0191] In some embodiments, the dendrimer conjugate of Formula (II) is of the formula:, or a pharmaceutically acceptable salt thereof. 72 / 156 13813260

[0192] In some embodiments, the dendrimer conjugate of Formula (II) is of the formula:, or a pharmaceutically acceptable salt thereof.

[0193] In some embodiments, the dendrimer conjugate of Formula (II) is of the formula:, or a pharmaceutically acceptable salt thereof.

[0194] In some embodiments, the dendrimer conjugate of Formula (II) is of the formula:, or a pharmaceutically acceptable salt thereof.

[0195] In some embodiments, the dendrimer conjugate of Formula (II) is of the formula:, or a pharmaceutically acceptable salt thereof.

[0196] In some embodiments, the dendrimer conjugate of Formula (II) is of the formula: 73 / 156 13813260, or a pharmaceutically acceptable salt thereof.

[0197] In some embodiments, the dendrimer conjugate of Formula (II) is of the formula:, or a pharmaceutically acceptable salt thereof.

[0198] In some embodiments, the dendrimer conjugate of Formula (II) is of the formula:, or a pharmaceutically acceptable salt thereof.

[0199] In some embodiments, the dendrimer conjugate of Formula (II) is of the formula:, or a pharmaceutically acceptable salt thereof.

[0200] In some embodiments, the dendrimer conjugate of Formula (II) is of the formula: 74 / 156 13813260, or a pharmaceutically acceptable salt thereof.

[0201] In some embodiments, the dendrimer conjugate of Formula (II) is of the formula:, or a pharmaceutically acceptable salt thereof.

[0202] In some embodiments, the dendrimer conjugate of Formula (II) is of the formula:, or a pharmaceutically acceptable salt thereof.

[0203] In some embodiments, the dendrimer conjugate of Formula (II) is of the formula:, or a pharmaceutically acceptable salt thereof.

[0204] In some embodiments, the dendrimer conjugate of Formula (II) is of the formula: 75 / 156 13813260, or a pharmaceutically acceptable salt thereof.

[0205] In some embodiments, the dendrimer conjugate of Formula (II) is of the formula:, or a pharmaceutically acceptable salt thereof.

[0206] In some embodiments, the dendrimer conjugate of Formula (II) is of the formula:, or a pharmaceutically acceptable salt thereof.

[0207] In some embodiments, the dendrimer conjugate of Formula (II) is of the formula:, or a pharmaceutically acceptable salt thereof.

[0208] In some embodiments, the dendrimer conjugate of Formula (II) is of the formula: 76 / 156 13813260, or a pharmaceutically acceptable salt thereof.

[0209] In some embodiments, the dendrimer conjugate of Formula (II) is of the formula:, or a pharmaceutically acceptable salt thereof.

[0210] In some embodiments, the dendrimer conjugate of Formula (II) is of the formula:, or a pharmaceutically acceptable salt thereof.

[0211] In some embodiments, the dendrimer conjugate of Formula (II) is of the formula:, or a pharmaceutically acceptable salt thereof.

[0212] In some embodiments, the dendrimer conjugate of Formula (II) is of the formula: 77 / 156 13813260, or a pharmaceutically acceptable salt thereof.

[0213] In some embodiments, the dendrimer conjugate of Formula (II) is of the formula:, or a pharmaceutically acceptable salt thereof.

[0214] In some embodiments, the dendrimer conjugate of Formula (II) is of the formula:, or a pharmaceutically acceptable salt thereof.

[0215] In some embodiments, the dendrimer conjugate of Formula (II) is of the formula: ,

[0216] In some embodiments, the dendrimer conjugate of Formula (II) is of the formula: 78 / 156 13813260, or a pharmaceutically acceptable salt thereof.

[0217] In some embodiments, the dendrimer conjugate of Formula (II) is of the formula:or a pharmaceutically acceptable salt thereof.

[0218] In some embodiments, the dendrimer conjugate of Formula (II) is of the formula:, or a pharmaceutically acceptable salt thereof.

[0219] In some embodiments, the dendrimer conjugate of Formula (II) is of the formula:, or a pharmaceutically acceptable salt thereof.

[0220] In some embodiments, the dendrimer conjugate of Formula (II) is of the formula: 79 / 156 13813260, or a pharmaceutically acceptable salt thereof.

[0221] In some embodiments of the dendrimer conjugate of Formula (II ) or (II), p is 0.

[0222] In some embodiments, the dendrimer conjugate is of the formula:, or a pharmaceutically acceptable salt thereof.

[0223] In some embodiments, the dendrimer conjugate is of the formula:, or a pharmaceutically acceptable salt thereof.

[0224] In some embodiments, the dendrimer conjugate is of the formula:, or a pharmaceutically acceptable salt thereof.

[0225] In some embodiments, the dendrimer conjugate of Formula (II′) is of the formula: 80 / 156 13813260, or a pharmaceutically acceptable salt thereof.

[0226] In some embodiments, the dendrimer conjugate of Formula (II′) is of the formula:, or a pharmaceutically acceptable salt thereof.

[0227] In some embodiments, the dendrimer conjugate of Formula (II′) is of the formula:, or a pharmaceutically acceptable salt thereof.

[0228] In some embodiments, the dendrimer conjugate of Formula (II′) is of the formula: 81 / 156 13813260, or a pharmaceutically acceptable salt thereof.

[0229] In some embodiments, the dendrimer conjugate of Formula (II′) is of the formula:, or a pharmaceutically acceptable salt thereof.

[0230] In some embodiments, the dendrimer conjugate of Formula (II′) is of the formula:, or a pharmaceutically acceptable salt thereof.

[0231] In some embodiments, the dendrimer conjugate of Formula (II′) is of the formula: 82 / 156 13813260, or a pharmaceutically acceptable salt thereof.

[0232] In some embodiments, the dendrimer conjugate of Formula (II′) is of the formula:, or a pharmaceutically acceptable salt thereof.

[0233] In some embodiments, the dendrimer conjugate of Formula (II′) is of the formula:, or a pharmaceutically acceptable salt thereof.

[0234] In some embodiments, the dendrimer conjugate of Formula (II′) is of the formula:, 83 / 156 13813260or a pharmaceutically acceptable salt thereof.

[0235] In some embodiments, the dendrimer conjugate of Formula (II′) is of the formula:, or a pharmaceutically acceptable salt thereof.

[0236] In some embodiments, the dendrimer conjugate of Formula (II′) is of the formula:, or a pharmaceutically acceptable salt thereof.

[0237] In some embodiments, the dendrimer conjugate of Formula (II′) is of the formula:, or a pharmaceutically acceptable salt thereof.

[0238] In some embodiments, the dendrimer conjugate of Formula (II′) is of the formula: 84 / 156 13813260, or a pharmaceutically acceptable salt thereof.

[0239] In some embodiments, the dendrimer conjugate of Formula (II′) is of the formula:, or a pharmaceutically acceptable salt thereof.

[0240] In some embodiments, the dendrimer conjugate of Formula (II′) is of the formula:, or a pharmaceutically acceptable salt thereof.

[0241] In some embodiments, the dendrimer conjugate of Formula (II′) is of the formula:, or a pharmaceutically acceptable salt thereof. 85 / 156 13813260

[0242] In some embodiments, the dendrimer conjugate of Formula (II′) is of the formula: ,

[0243] In some embodiments, the dendrimer conjugate of Formula (II′) is of the formula:, or a pharmaceutically acceptable salt thereof.

[0244] In some embodiments, the dendrimer conjugate of Formula (II′) is of the formula:, or a pharmaceutically acceptable salt thereof.

[0245] In some embodiments, the dendrimer conjugate of Formula (II′) is of the formula: 86 / 156 13813260, or a pharmaceutically acceptable salt thereof.

[0246] In some embodiments, the dendrimer conjugate of Formula (II′) is of the formula:, or a pharmaceutically acceptable salt thereof.

[0247] In some embodiments, the dendrimer conjugate of Formula (II′) is of the formula:, or a pharmaceutically acceptable salt thereof.

[0248] In some embodiments, the dendrimer conjugate of Formula (II′) is of the formula:, or a pharmaceutically acceptable salt thereof. 87 / 156 13813260

[0249] In some embodiments, the dendrimer conjugate of Formula (II′) is of the formula:, or a pharmaceutically acceptable salt thereof.

[0250] In some embodiments, the dendrimer conjugate of Formula (II′) is of the formula:, or a pharmaceutically acceptable salt thereof.

[0251] In some embodiments, the dendrimer conjugate of Formula (II′) is of the formula:, or a pharmaceutically acceptable salt thereof.

[0252] In some embodiments, the dendrimer conjugate of Formula (II′) is of the formula: 88 / 156 13813260, or a pharmaceutically acceptable salt thereof.

[0253] In some embodiments, the dendrimer conjugate of Formula (II′) is of the formula:, or a pharmaceutically acceptable salt thereof.

[0254] In some embodiments, the dendrimer conjugate of Formula (II′) is of the formula:, or a pharmaceutically acceptable salt thereof.

[0255] In some embodiments, the dendrimer conjugate of Formula (II′) is of the formula: 89 / 156 13813260, or a pharmaceutically acceptable salt thereof.

[0256] In some embodiments, the dendrimer conjugate of Formula (II′) is of the formula:, or a pharmaceutically acceptable salt thereof.

[0257] In some embodiments, the dendrimer conjugate of Formula (II) is of the formula: 90 / 156 13813260, or a pharmaceutically acceptable salt thereof.

[0258] In some embodiments, the dendrimer conjugate of Formula (II) is of the formula:, or a pharmaceutically acceptable salt thereof.

[0259] In some embodiments, the dendrimer conjugate of Formula (II) is of the formula:, or a pharmaceutically acceptable salt thereof.

[0260] In some embodiments, the dendrimer conjugate of Formula (II) is of the formula: 91 / 156 13813260, or a pharmaceutically acceptable salt thereof.

[0261] In some embodiments, the dendrimer conjugate of Formula (II) is of the formula:, or a pharmaceutically acceptable salt thereof.

[0262] In some embodiments, the dendrimer conjugate of Formula (II) is of the formula:, or a pharmaceutically acceptable salt thereof.

[0263] In some embodiments, the dendrimer conjugate of Formula (II) is of the formula: 92 / 156 13813260, or a pharmaceutically acceptable salt thereof.

[0264] In some embodiments, the dendrimer conjugate of Formula (II) is of the formula:, or a pharmaceutically acceptable salt thereof.

[0265] In some embodiments, the dendrimer conjugate of Formula (II) is of the formula:, or a pharmaceutically acceptable salt thereof.

[0266] In some embodiments, the dendrimer conjugate of Formula (II) is of the formula: 93 / 156 13813260, or a pharmaceutically acceptable salt thereof.

[0267] In some embodiments, the dendrimer conjugate of Formula (II) is of the formula:, or a pharmaceutically acceptable salt thereof.

[0268] In some embodiments, the dendrimer conjugate of Formula (II) is of the formula:, or a pharmaceutically acceptable salt thereof.

[0269] In some embodiments, the dendrimer conjugate of Formula (II) is of the formula: 94 / 156 13813260, or a pharmaceutically acceptable salt thereof.

[0270] In some embodiments, the dendrimer conjugate of Formula (II) is of the formula:, or a pharmaceutically acceptable salt thereof.

[0271] In some embodiments, the dendrimer conjugate of Formula (II) is of the formula:, or a pharmaceutically acceptable salt thereof.

[0272] In some embodiments, the dendrimer conjugate of Formula (II) is of the formula: 95 / 156 13813260, or a pharmaceutically acceptable salt thereof.

[0273] In some embodiments, the dendrimer conjugate of Formula (II) is of the formula:, or a pharmaceutically acceptable salt thereof.

[0274] In some embodiments, the dendrimer conjugate of Formula (II) is of the formula:, or a pharmaceutically acceptable salt thereof.

[0275] In some embodiments, the dendrimer conjugate of Formula (II) is of the formula:, or a pharmaceutically acceptable salt thereof. 96 / 156 13813260

[0276] In some embodiments, the dendrimer conjugate of Formula (II) is of the formula:, or a pharmaceutically acceptable salt thereof.

[0277] In some embodiments, the dendrimer conjugate of Formula (II) is of the formula:, or a pharmaceutically acceptable salt thereof.

[0278] In some embodiments, the dendrimer conjugate of Formula (II) is of the formula:, or a pharmaceutically acceptable salt thereof.

[0279] In some embodiments, the dendrimer conjugate of Formula (II) is of the formula:, 97 / 156 13813260or a pharmaceutically acceptable salt thereof.

[0280] In some embodiments, the dendrimer conjugate of Formula (II) is of the formula:, or a pharmaceutically acceptable salt thereof.

[0281] In some embodiments, the dendrimer conjugate of Formula (II) is of the formula:, or a pharmaceutically acceptable salt thereof.

[0282] In some embodiments, the dendrimer conjugate of Formula (II) is of the formula:, or a pharmaceutically acceptable salt thereof.

[0283] In some embodiments, the dendrimer conjugate of Formula (II) is of the formula: 98 / 156 13813260, or a pharmaceutically acceptable salt thereof.

[0284] In some embodiments, the dendrimer conjugate of Formula (II) is of the formula:, or a pharmaceutically acceptable salt thereof.

[0285] In some embodiments, the dendrimer conjugate of Formula (II) is of the formula:, or a pharmaceutically acceptable salt thereof.

[0286] In some embodiments, the dendrimer conjugate of Formula (II) is of the formula: 99 / 156 13813260, or a pharmaceutically acceptable salt thereof.

[0287] In some embodiments, the dendrimer conjugate of Formula (II) is of the formula:, or a pharmaceutically acceptable salt thereof.

[0288] In some embodiments, the dendrimer conjugate of Formula (II) is of the formula:, or a pharmaceutically acceptable salt thereof.

[0289] In some embodiments, the dendrimer conjugate of Formula (II) is of the formula: 100 / 156 13813260, or a pharmaceutically acceptable salt thereof.

[0290] In some embodiments, the dendrimer conjugate of Formula (II) is of the formula:, or a pharmaceutically acceptable salt thereof.

[0291] In some embodiments, the dendrimer conjugate of Formula (II) is of the formula:, or a pharmaceutically acceptable salt thereof.

[0292] In some embodiments, the dendrimer conjugate of Formula (II) is of the formula: 101 / 156 13813260, or a pharmaceutically acceptable salt thereof.

[0293] In some embodiments, the dendrimer conjugate of Formula (II) is of the formula:, or a pharmaceutically acceptable salt thereof.

[0294] In some embodiments, the dendrimer conjugate of Formula (II) is of the formula:, or a pharmaceutically acceptable salt thereof.

[0295] In some embodiments, the dendrimer conjugate of Formula (II) is of the formula: 102 / 156 13813260, or a pharmaceutically acceptable salt thereof.

[0296] In some embodiments, the dendrimer conjugate is of the formula as depicted in any one of FIGs.28A-28H.

[0297] In some embodiments, 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, 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, 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. In some embodiments, the dendrimer conjugate of Formula (II′) or (II) is in the form of a dendrimer conjugate. Compositions

[0298] 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.

[0299] 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 13813260inhalation; and / or as an oral spray, nasal spray, and / or aerosol. Specifically contemplated routes are oral administration, intravenous administration (e.g., systemic intravenous injection), regional administration via blood and / or lymph supply, and / or direct administration to an affected site. In general, the most appropriate route of administration will depend upon a variety of factors including the nature of the agent (e.g., its stability in the environment of the gastrointestinal tract), and / or the condition of the subject (e.g., whether the subject is able to tolerate oral administration).

[0300] In some embodiments, a composition comprises a dendrimer conjugate disclosed herein and one or more pharmaceutically acceptable excipients. Examples of 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.

[0301] In some embodiments, dendrimer conjugates and compositions provided herein are formulated for use in radionuclide imaging and / or radiotherapy. In some embodiments, 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. In some embodiments, a composition to be administered to a subject is in a volume of between about 0.01 mL and about 10 mL. In some embodiments, 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. Methods of Imaging

[0302] Provided herein are methods of using the dendrimer conjugates disclosed herein. In some aspects, the disclosure provides methods of imaging a tissue in a subject. In certain embodiments, the tissue in the subject is a tissue of the central nervous system. In some embodiments, the subject has or is suspected of having a neurological disorder, an autoimmune disorder, or a cancer. In some embodiments, the subject has or is suspected of having a neurodegenerative disorder. In some embodiments, 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. In some embodiments, the 104 / 156 13813260neurodegenerative disorder is multiple sclerosis (MS). In some embodiments, the neurodegenerative disorder is relapsing remitting MS, primary progressive MS, or secondary progressive MS.

[0303] In one aspect, provided herein are methods of imaging a tissue in a subject, the method comprising: administering the dendrimer conjugate or composition thereof to a subject; and obtaining an image representation of a tissue in the subject.

[0304] As used herein, 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. In some embodiments, an image representation is a two-dimensional depiction. In some embodiments, an image representation is a three-dimensional depiction. Examples of 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. In some embodiments, 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.

[0305] In some embodiments, 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. In some embodiments, 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.

[0306] In some embodiments, the image representation can be used to diagnose, monitor, and / or evaluate a disease or disorder in a subject. For example, in some embodiments, a disease or disorder in a subject can be identified or diagnosed by detecting the dendrimer conjugate in the image representation. In some embodiments, 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. In some embodiments, the image representation is one of a series of image representations obtained at different time points. By comparing 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. In some embodiments, one or more image representations can be obtained before, during, and / or after a particular therapeutic regimen. Thus, in some embodiments, the image representation can be used to monitor or evaluate the effects of a particular therapy. 105 / 156 13813260

[0307] In some embodiments, 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.

[0308] In certain embodiments, detection of the dendrimer conjugate in the image representation is indicative of one or more sites of inflammation in the tissue of the subject.

[0309] In some embodiments, the one or more sites of inflammation in the tissue of the subject are associated with an inflammatory or autoimmune disease. In certain embodiments, 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 fibrosis, idiopathic thrombocytopenia purpura, IgA nephropathy, insulin-dependent diabetes, Meniere’s disease, mixed connective tissue disease, multiple sclerosis, myasthenia gravis, pemphigus vulgaris, pernicious anemia, polyarteritis nodosa, polychondritis, polyglandular syndrome, polymyalgia rheumatica, polymyositis and dermatomyositis, primary agammaglobulinemia, primary biliary cirrhosis, psoriasis, Raynaud’s phenomenon, Reiter’s syndrome, rheumatic fever, rheumatoid arthritis, sarcoidosis, scleroderma, Sjogren’s syndrome, stiff-man syndrome, systemic lupus erythematosus, Takayasu arteritis, temporal arteritis, ulcerative colitis, uveitis, vasculitis, vitiligo, and Wegener’s granulomatosis.

[0310] In certain embodiments, 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. In some embodiments, the one or more sites of neuroinflammation in the central nervous system of the subject are associated with a neurodegenerative disorder. In some embodiments, 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. In some embodiments, the neurodegenerative disorder is multiple sclerosis (MS). In some embodiments, the neurodegenerative disorder is relapsing remitting MS, primary progressive MS, or secondary progressive MS. 106 / 156 13813260

[0311] In some embodiments, 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. In some embodiments, the one or more sites of inflammation in the tissue of the subject are associated with multi-organ dysfunction, such as neuroinflammation. In some embodiments, 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. In some embodiments, the one or more sites of inflammation in the tissue of the subject are associated with inflammation characterized by cytokine storm.

[0312] In some embodiments, detection of the dendrimer conjugate in the image representation is indicative of one or more cancer cells in the tissue of the subject. In some embodiments, the one or more cancer cells comprise tumor-associated macrophages. In some embodiments, the one or more cancer cells comprise primary tumor cells or metastasized cancer cells.

[0313] In some embodiments, detection of the dendrimer conjugate in the image representation is indicative of a cancer in the tissue of the subject. In some embodiments, 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.

[0314] In certain embodiments, the image representation is obtained by imaging the subject with a molecular imaging device. In certain embodiments, the molecular imaging device comprises a gamma camera for positron emission tomography (PET) scanning or single photon emission computed tomography (SPECT).

[0315] In some embodiments, 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.

[0316] In some embodiments, after administration of the dendrimer conjugate, 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 13813260administered 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

[0317] Provided herein are methods of treatment using the dendrimer conjugates disclosed herein. In one aspect, provided herein are methods of treating a cancer in a subject, the method comprising administering a dendrimer conjugate disclosed herein or composition thereof to a subject. In some embodiments, the subject has a primary tumor and / or a metastasized cancer. In some embodiments, the subject has a brain tumor and / or brain metastasis. In some embodiments, the cancer 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. In certain embodiments, the subject has a primary tumor and / or a metastasized cancer. In some embodiments, the subject has a brain tumor and / or brain metastasis.

[0318] 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.

[0319] 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 plasmacytoma; Waldenström’s macroglobulinemia; monoclonal gammopathy of undetermined significance; benign monoclonal gammopathy; heavy chain disease; bone and connective tissue sarcomas such as, but not limited to, bone sarcoma, osteosarcoma, chondrosarcoma, Ewing’s sarcoma, malignant giant cell tumor, fibrosarcoma of bone, chordoma, periosteal sarcoma, soft-tissue sarcomas, angiosarcoma (hemangiosarcoma), fibrosarcoma, Kaposi’s sarcoma, leiomyosarcoma, liposarcoma, lymphangiosarcoma, neurilemmoma, rhabdomyosarcoma, synovial sarcoma; brain tumors including, but not limited 108 / 156 13813260to, glioma, astrocytoma, brain stem glioma, ependymoma, oligodendroglioma, nonglial tumor, acoustic neurinoma, craniopharyngioma, medulloblastoma, meningioma, pineocytoma, pineoblastoma, primary brain lymphoma; breast cancer including, but not limited to, adenocarcinoma, lobular (small cell) carcinoma, intraductal carcinoma, medullary breast cancer, mucinous breast cancer, tubular breast cancer, papillary breast cancer, Paget’s disease, and inflammatory breast cancer; adrenal cancer, including, but not limited to, pheochromocytom and adrenocortical carcinoma; thyroid cancer such as but not limited to papillary or follicular thyroid cancer, medullary thyroid cancer and anaplastic thyroid cancer; pancreatic cancer, including, but not limited to, insulinoma, gastrinoma, glucagonoma, vipoma, somatostatin-secreting tumor, and carcinoid or islet cell tumor; pituitary cancers including, but not limited to, Cushing’s disease, prolactin-secreting tumor, acromegaly, and diabetes insipius; eye cancers including, but not limited to, ocular melanoma such as iris melanoma, choroidal melanoma, and cilliary body melanoma, and retinoblastoma; vaginal cancers, including, but not limited to, squamous cell carcinoma, adenocarcinoma, and melanoma; vulvar cancer, including, but not limited to, squamous cell carcinoma, melanoma, adenocarcinoma, basal cell carcinoma, sarcoma, and Paget’s disease; cervical cancers including, but not limited to, squamous cell carcinoma, and adenocarcinoma; uterine cancers including, but not limited to, endometrial carcinoma and uterine sarcoma; ovarian cancers including, but not limited to, ovarian epithelial carcinoma, borderline tumor, germ cell tumor, and stromal tumor; esophageal cancers including, but not limited to, squamous cancer, adenocarcinoma, adenoid cyctic carcinoma, mucoepidermoid carcinoma, adenosquamous carcinoma, sarcoma, melanoma, plasmacytoma, verrucous carcinoma, and oat cell (small cell) carcinoma; stomach cancers including, but not limited to, adenocarcinoma, fungating (polypoid), ulcerating, superficial spreading, diffusely spreading, malignant lymphoma, liposarcoma, fibrosarcoma, and carcinosarcoma; colon cancers; rectal cancers; liver cancers including, but not limited to, hepatocellular carcinoma and hepatoblastoma, gallbladder cancers including, but not limited to, adenocarcinoma; cholangiocarcinomas including, but not limited to, papillary, nodular, and diffuse; lung cancers including, but not limited to, non-small cell lung cancer, squamous cell carcinoma (epidermoid carcinoma), adenocarcinoma, large-cell carcinoma and small-cell lung cancer; testicular cancers including, but not limited to, germinal tumor, seminoma, anaplastic, classic (typical), spermatocytic, nonseminoma, embryonal carcinoma, teratoma carcinoma, choriocarcinoma (yolk-sac tumor), prostate cancers including, but not limited to, adenocarcinoma, leiomyosarcoma, and rhabdomyosarcoma; penal cancers; oral cancers including, but not limited to, squamous cell carcinoma; basal cancers; salivary gland cancers 109 / 156 13813260including, but not limited to, adenocarcinoma, mucoepidermoid carcinoma, and adenoidcystic carcinoma; pharynx cancers including, but not limited to, squamous cell cancer, and verrucous; skin cancers including, but not limited to, basal cell carcinoma, squamous cell carcinoma and melanoma, superficial spreading melanoma, nodular melanoma, lentigo malignant melanoma, acral lentiginous melanoma; kidney cancers including, but not limited to, renal cell cancer, adenocarcinoma, hypernephroma, fibrosarcoma, transitional cell cancer (renal pelvis and / or uterer); Wilms’ tumor; bladder cancers including, but not limited to, transitional cell carcinoma, squamous cell cancer, adenocarcinoma, carcinosarcoma.

[0320] In some embodiments, 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 β-particle and α-particle emitters. In some embodiments, the one or more radionuclides are selected from90Y,131I,153Sm,166Ho,177Lu,186Re,203Pb,211At,212Pb,223Ra,225Ac, and227Th, or ion thereof. In some embodiments, the one or more radionuclides comprise90Y. In some embodiments, the one or more radionuclides comprise225Ac,203Pb, or177Lu. In some embodiments, the one or more radionuclides comprise225Ac. In some embodiments, the one or more radionuclides comprise203Pb. In some embodiments, the one or more radionuclides comprise177Lu.

[0321] In some embodiments, a radionuclide-conjugated dendrimer is further conjugated to one or more anti-tumor drugs. Exemplary 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.

[0322] 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, bleomycin, fadrozole, mitomycin, fludarabine, prednisone, pentostatin, mitoxantrone, medroxyprogesterone, mercaptopurine, mitotane, zinostatin, rapamycin, cyclosporine, mycophenolate mofetil, and mizoribine.

[0323] Other exemplary anti-tumor drugs include inhibitors targeting one or more of EGFR, ERBB2, VEGFRs, Kit, PDGFRs, ABL, SRC and mTOR. In some embodiments, one or more anti-tumor drugs are inhibitors such as crizotinib, ceritinib, alectinib, brigatinib, bosutinib, 110 / 156 13813260dasatinib, imatinib, nilotinib, vemurafenib, dabrafenib, ibrutinib, palbociclib, sorafenib, ribociclib, cabozantinib, gefitinib, erlotinib, lapatinib, vandetanib, afatinib, osimertinib, ruxolitinib, tofacitinib, trametinib, axitinib, lenvatinib, nintedanib, pazopanib, regorafenib, sunitinib, vandetanib, dacomitinib, and ponatinib. In some embodiments, one or more anti- tumor drugs are tyrosine kinase inhibitors such as HER2 inhibitors, EGFR tyrosine kinase inhibitors. Exemplary EGFR tyrosine kinase inhibitors include gefitinib, erlotinib, afatinib, dacomitinib, and osimertinib.

[0324] In some embodiments, 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.

[0325] 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. In some embodiments, doses can range from a single dose of about 30-50 mCi to a cumulative dose of up to about 3 Ci.

[0326] 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

[0327] 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. For example, 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. In some embodiments, the symptom, 111 / 156 13813260pharmacologic, or physiologic indicator is measured in a subject prior to treatment, and again one or more times after treatment is initiated. In some embodiments, 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). In some embodiments, the effect of the treatment is compared to a conventional treatment that is known the art. In some embodiments, an untreated control subject suffers from the same disease or condition as the treated subject. Dosages and Effective Amounts

[0328] Dosage and dosing regimens 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.

[0329] In some embodiments, 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.

[0330] A pharmaceutical composition including a therapeutically effective amount of the dendrimer compositions and a pharmaceutically acceptable diluent, carrier or excipient is described. In some embodiments, 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.

[0331] 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.

[0332] 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

[0333] 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.

[0334] In some embodiments, 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. In some embodiments, dosages are administered about once or twice every week, every two weeks, every three weeks, or every four weeks. In some embodiments, 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.

[0335] It will be understood by those of ordinary skill that a dosing regimen can be any length of time sufficient to treat the disorder in the subject. In some embodiments, 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

[0336] In some aspects, the disclosure provides a kit comprising a dendrimer conjugate or composition described herein. In some embodiments, 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. In some embodiments, 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. The composition can be formulated as described above with reference to a particular treatment method and can be packaged in any convenient manner.

[0337] In some embodiments, 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. In some embodiments, the kit comprises a single container comprising a composition of the disclosure. In some embodiments, the kit comprises two or more (e.g., 2, 3, 4, 5, or more) containers comprising the composition. In some embodiments, the components of a kit are packaged in solution or lyophilized form. In some embodiments, 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. In some embodiments, the kit comprises at 113 / 156 13813260least one container comprising one or more stabilizers, bulking agents (e.g., mannitol), or other additives known in the art.

[0338] The present invention will be further understood by reference to the following non- limiting examples. EXAMPLES

[0339] In order that the present disclosure may be more fully understood, the following examples are set forth. The examples described in this Application are offered to illustrate the compounds, pharmaceutical compositions, and methods provided herein and are not to be construed in any way as limiting their scope. GC Method for Examples 1 and 2

[0340] 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: 250oC 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: 300oC 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 13813260Example 1: Synthesis of PAMAM G4-OH-Alkyne3115 / 156 13813260

[0341] 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. After this time, the solution was diluted to half the concentration with water and subjected to purification by ultrafiltration providing the product as an aqueous solution. 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 by1H-NMR and 116 / 156 1381326013C-NMR to determine the degree of alkyne functionalization. The remaining solid was dissolved in methanol to generate a 15.3 wt% methanolic solution. A summary of results is provided below in Table E1.

[0342] Table E1: Characterization SummaryExample 2: Synthesis of PAMAM G4-OH-Alkyne10117 / 156 13813260

[0343] 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 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. After this time, the solution was diluted to half the concentration with water and 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 118 / 156 13813260foam was taken for analysis by1H-NMR and13C-NMR to determine the degree of alkyne functionalization. The remaining solid was dissolved in methanol to generate a 15.3 wt% methanolic solution. A summary of results is provided below in Table E2.

[0344] Table E2: Characterization SummaryExample 3: Synthesis of OP-801

[0345] A 1 L jacketed vessel was charged with a 228.8 g of 15.3 wt% PAMAM G4-OH- Alkyne10in methanol. Then it was diluted with 501 mL water and 70.7 g of 5 wt% 1-azido-4- fluoropropane (e.g., Lot# Enamine Inc.2021-0429913) in THF (1.5 equiv) was added. Then, 6.89 g of sodium ascorbate (1.5 equiv) was added followed by 23.2 mL of 0.1 M copper sulfate pentahydrate solution (0.1 equiv). 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. After filtration to remove the silica, 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 by1H-NMR and13C-NMR to determine the degree of alkyne functionalization. The remaining solid was dissolved in pure ethanol to generate a 16.3 wt% ethanolic solution. Then this ethanolic solution was further diluted in volumetric flask to make 119 / 156 1381326050 mg / mL ethanolic solution of OP-801. The material made was then subjected to sterile filtration (e.g., VWR 500 mL 0.2 µm pes filter unit, part# 514-0332) to obtain final OP-801. A summary of results for is provided in Table E3.

[0346] Table E3: Characterization Summary

[0347] UPLC method used for Table E3 appears below. The reagents used include: 1. Water: HPLC grade 2. Acetonitrile: HPLC grade 3. Trifluoroacetic acid: HPLC grade The solutions used include: 1. Diluent: MiliQ water 2. Mobile phase: A. 0.05% Trifluoroacetic acid in Water B. 0.05% Trifluoroacetic acid in Acetonitrile 3. Sample Solutions: the sample solution at a target concentration of approximately 2 mg / mL. 4. Blank: Diluent. The chromatographic conditions used include: Column: ACE Excel 3 Super C18, LC column, 50 x 3 x 3 µm Temperature: 40 °C Flow Rate: 1.27 mL / min 120 / 156 13813260Detection: A: UV at 210 nm; 4.8 nm bandwidth B: UV at 220 nm; 4.8 nm bandwidth Injection Volume: 10 mL Run Time: 12.3 min The gradient used was:Example 4: Chelator Synthesis Procedure A1 Synthesis

[0348] Procedure A1 can be utilized to synthesize a variety of moieties comprising a chelator which are ready for further functionalization. Procedure A1 can be used to synthesize the precursor to -RB-L2-R1in Formulae (I′), (I), (II′), and (II) wherein the tetrazine in Procedure A1 is reacted to ultimately form one of the polycyclic rings in RB. The compounds in FIG.29A may be synthesized via Procedure A1 and used throughout Example 5 and 6.

[0349] 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 (30). A solution of 2- (4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecan-1-yl)acetic acid (28) (1.15 g, 2.0 mmol), (4-(6-methyl-1,2,4,5-tetrazin-3-yl)phenyl)methanamine (29) (443 mg, 2.2 mmol), and N,N-diisopropylethylamine (0.70 mL, 4.0 mmol) in N,N-dimethylformamide (5 mL) was stirred, and HATU (1.14 g, 3.0 mmol) was added. The reaction mixture was stirred at room temperature overnight while protecting from light. The mixture was then diluted with 121 / 156 13813260water and purified by reverse-phase chromatography (C18, water / acetonitrile) to afford 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 (30) as a bright pink solid.1H-NMR (500 MHz, (CD3)2SO) δ 9.08 (t, 1H, J = 6.1 Hz), 8.42 (d, 2H, J = 8.2 Hz), 7.52 (d, 2H, J = 8.2 Hz), 4.47 (d, 2H, J = 5.3 Hz), 3.14 (s, 4H), 3.07-3.04 (m, 4H), 2.99 (s, 3H), 2.73-2.62 (m, 14H), 2.49-2.47 (m, 2H), 1.37 (s, 18H), 1.33 (s, 9H).

[0350] 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 (DOTA-Tetrazine, 13). 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 (30) (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. The 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.1H-NMR (500 MHz, (CD3)2SO) δ 9.05 (s, 1H), 8.45 (d, 2H, J = 8.2 Hz), 7.59 (d, 2H, J = 8.2 Hz), 4.48 (d, 2H, J = 5.3 Hz), 4.09-3.96 (m, 4H), 3.64 (s, 4H), 3.36 (s, 8H), 3.15 (s, 8H), 3.00 (s, 3H).

[0351] The following are also synthesized pursuant to Procedure A1:

[0352] NOTA-Tetrazine (9). Synthesis according to Procedure A1, see synthesis of (13). 122 / 156 13813260

[0353] NODAGA-Tetrazine (11). Synthesis according to Procedure A1, see synthesis of (13).

[0354] MACROPA-Tetrazine (13). Synthesis according to Procedure A1, see synthesis of (13). Procedure A2 Synthesis

[0355] 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 -RB-L2-R1in Formulae (I′), (I), (II′), and (II) wherein an azide installed in Procedure A2 is reacted to ultimately form one of the polycyclic rings in RB.

[0356] DOTA-PEG5-azide (44). Synthesized according to Journal of the American Chemical Society (2012), 134(24), 9832-9835). 123 / 156 13813260Example 5: Dendrimer Synthesis (Procedure B Synthesis) Procedure B1 Synthesis

[0357] 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 RBin Formulae (I′), (I), (II′), and (II).

[0358] D5.5-CO2Me (3). To a reaction vessel was added methyl acrylate (2) (22.5 grams, 0.781 mmol) followed by MeOH (113 mL). The solution was cooled in an ice bath and a premixed solution of D5-NH2 (1) (made by mixing 81.2 grams of 27.7% wt / wt D5-NH2 (1) in MeOH and MeOH (50 mL)) was added dropwise via addition funnel over 2.5 hours. The reaction was allowed to come to room temperature and was stirred for 7 days under a nitrogen atmosphere protected from light. The solvent was removed under reduced pressure to give D5.5-CO2Me (3) (39.9 grams, 0.784 mmol, 100% yield) as an amorphous solid.

[0359] D6-OH-3-NH2 (6). To a reaction vessel was added NH2-PEG2-NH2 (4) (1.17 grams, 7.90 mmol) and MeOH (10 mL). Ethanolamine (5) (23.8 grams, 389 mmol) was then added followed by a solution of D5.5-CO2Me (3) (3.86 grams, 0.0760 mmol) in MeOH (25 mL). The resulting solution was stirred at room temperature for 6 days. The solution was diluted with water (24x). The low molecular weight impurities were removed and the solvent was exchanged to water using tangential flow filtration (TFF) (10 kDa membrane). The resulting aqueous retentate was frozen and the water was removed through lyophilization to give D6- OH-3-NH2 (6) (4.0 grams, 0.068 mmol, 90% yield). 124 / 156 13813260

[0360] 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). The low molecular weight impurities were removed and the solvent was exchanged to water using tangential flow filtration (TFF) (10 kDa membrane). The resulting aqueous retentate was frozen and the water was removed through lyophilization to give D6-OH-3-TCO (8) (526 mg, 0.00882 mmol, 96% yield).

[0361] 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. The reaction was diluted with H2O (40 mL). The low molecular weight impurities were removed using tangential flow filtration (TFF) (10 kDa membrane). The resulting aqueous retentate was frozen and the water was removed through lyophilization to give D6-OH-3- NOTA (10) (175 mg, 0.00287 mmol, 73% yield).

[0362] D6-OH-3-NODAGA (12) (also referred to as S11ND3M3). D6-OH-3-TCO (8) (95 mg, 0.00159 mmol) was dissolved in water (5 mL). NODAGA-Tetrazine.3TFA (11) (4.4 mg, 0.0080 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). The resulting 125 / 156 13813260aqueous retentate was frozen and the water was removed through lyophilization to give D6- OH-3-NODAGA (12) (95 mg, 0.0016 mmol, 98% yield).

[0363] D6-OH-3-DOTA (14) (also referred to as S10DT3M3). 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). 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).

[0364] 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). The resulting aqueous retentate was frozen and the water was removed through lyophilization to give D5-OH-2-NOTA (16) (318 mg, 0.00103 mmol, 100% yield).

[0365] D4-OH-1-NOTA (18) (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 13813260stirred 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) (3 kDa membrane). The resulting aqueous retentate was frozen and the water was removed through lyophilization to give D4-OH-1-NOTA (18) (167 mg, 0.0110 mmol, 93% yield).

[0366] 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. The reaction was diluted with H2O (40 mL). The low molecular weight impurities were removed using tangential flow filtration (TFF) (3 kDa membrane). The resulting aqueous retentate was frozen and the water was removed through lyophilization to give D4-OH-3- NOTA (20) (115 mg, 0.00677 mmol, 78% yield).

[0367] D6-OH-3-MACROPA (21). Synthesis according to Procedure B as provided herein, such as that for D6-OH-3-DOTA (14). Procedure B2 Synthesis

[0368] Procedure B2 can be utilized to synthesize a variety of dendrimers comprising a chelator. 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 RBin Formulae (I′), (I), (II′), and (II).127 / 156 13813260

[0369] D6-OH-5-NH2 (41). To a reaction vessel was added NH2-PEG2-NH2 (4) (1.75 grams, 11.8 mmol) and MeOH (30 mL). Ethanolamine (5) (30.14 grams, 493.5 mmol) was then added followed by a solution of D5.5-CO2Me (3) (30.4% wt / wt in MeOH, 16.45 grams, 0.0983 mmol). The resulting solution was stirred at room temperature for 6 days. The solution was diluted with water (24x). The low molecular weight impurities were removed and the solvent was exchanged to water using tangential flow filtration (TFF) (10 kDa membrane). The resulting aqueous retentate was frozen and the water was removed through lyophilization to give D6-OH-5-NH2 (41) (5.30 grams, 0.0902 mmol, 92% yield).

[0370] D6-OH-5-DBCO (43). To a reaction vessel was added DIEA (18 mg, 0.14 mmol) and a solution of D6-5-NH2 (41) (950 mg, 0.0159 mmol) in DMAc (4 mL). A solution of DBCO- NHS ester (42) (51mg, 0.13 mmol) in DMAc (1 mL) was then added. The reaction was allowed to stir at room temperature for 24 hours protected from light. The reaction was then diluted with 16% wt / wt DMAc / water (50x). The low molecular weight impurities were removed and the solvent was exchanged to water using tangential flow filtration (TFF) (10 kDa membrane). The resulting aqueous retentate was frozen and the water was removed through lyophilization to give D6-OH-5-DBCO (43) (900 mg, 0.015 mmol, 94% yield).

[0371] 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) in DMAc (0.5 mL) 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). The low molecular weight impurities were removed and the solvent was exchanged to water using tangential flow filtration (TFF) (10 kDa membrane). The resulting aqueous retentate was frozen and the water was removed through lyophilization to give D6-OH-5-DOTA (45). 128 / 156 13813260Example 6: Radiolabeling (Procedure C Synthesis)

[0372] 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 R1is a chelator of a radionuclide, to a compound of Formula (I) or (II), wherein R1is a chelator comprising a radionuclide).

[0373] D6-OH-3-NOTA-64Cu (32). D6-OH-3-NOTA (10) was dissolved in 1M NaOAc buffer (pH = 5.0) to a final concentration of 5 mg / mL. The resulting solution was treated with64CuCl2 for 60 minutes at 37C to give D6-OH-3-NOTA-64Cu (32).97.1%64Cu labeling as determined by radio-HPLC (C-18).

[0374] D6-OH-3-NOTA-177Lu (38). D6-OH-3-NOTA (10) was dissolved in 1M NaOAc buffer (pH = 5.0) to a final concentration of 5 mg / mL. The resulting solution was treated with177LuCl3 for 60 minutes at 75C to give D6-OH-3-NOTA-177Lu (38).98.1%177Lu labeling as determined by radio-HPLC (C-18).

[0375] D6-OH-3-NODAGA-64Cu (33). D6-OH-3-NODAGA (12) was dissolved in 1M NaOAc buffer (pH = 5.0) to a final concentration of 5 mg / mL. The resulting solution was treated with64CuCl2 for 60 minutes at 37C to give D6-OH-3-NODAGA-64Cu (33).11.0%64Cu labeling as determined by radio-HPLC (C-18). 129 / 156 13813260

[0376] D6-OH-3-NODAGA-177Lu (39). D6-OH-3-NODAGA (12) was dissolved in 1M NaOAc buffer (pH = 5.0) to a final concentration of 5 mg / mL. The resulting solution wastreated with 177LuCl3for 60 minutes at 75C to give D6-OH-3-NODAGA-177Lu (39). 95.3%177Lu labeling as determined by radio-HPLC (C-18).

[0377] D6-OH-3-DOTA-64Cu (34). Synthesis according to Procedure C, for example, following the procedure of D6-OH-3-NODAGA-64Cu (33).

[0378] D6-OH-3-DOTA-177Lu (40). D6-OH-3-DOTA (12) was dissolved in 1M NaOAc buffer (pH = 5.0) to a final concentration of 5 mg / mL. The resulting solution was treated with177LuCl3 for 60 minutes at 75C to give D6-OH-3-DOTA-177Lu (39).98.3%177Lu labeling as determined by radio-HPLC (C-18).

[0379] D5-OH-2-NOTA-64Cu (35). D5-OH-2-NOTA (16) was dissolved in 1M NaOAc buffer (pH = 5.0) to a final concentration of 5 mg / mL. The resulting solution was treated with64CuCl2for 60 minutes at 37C to give D5-OH-2-NOTA-64Cu (35).60%64Cu labeling as determined by radio-HPLC (C-18). 130 / 156 13813260

[0381] D4-OH-3-NOTA-64Cu (37). D4-OH-3-NOTA (20) was dissolved in 0.2M NaOAc buffer (pH = 5.0) to a final concentration of 5 mg / mL. The resulting solution was treated with64CuCl2 for 120 minutes at 37C to give D6-OH-3-NOTA-64Cu (37).64%64Cu incorporation was obtained as determined by radio-HPLC (C-18). Example 7: Targeting Tumor Associated Macrophages

[0382] Two hydroxylated dendrimer (HD) sizes (G6 and G5, ~30 kDa) with NOTA covalently linked to surface hydroxyls and chelated to64Cu were used to evaluate in vivo tumor associated macrophages (TAM) uptake in a triple negative breast cancer (4T1) xenograft model.

[0383] 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))). The other HD (G6) was produced with three NOTA arms (HD6-NOTA (also referred to as S08NT3M and D6-OH-3-NOTA (10))). Both compounds were radiolabeled with64Cu. To track TAM uptake, HD5 and HD6 were labeled with 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. After tumors reached a mean size of 100 mm3, animals (4 / group) were balanced by tumor size across groups to receive an 10 MBq IV dose of 157 or 16 MBq / mg of64Cu-HD5-NOTA, or 182 or 20 MBq / mg of64Cu-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. After sacrifice, tumors were removed, and histology was performed for 131 / 156 13813260co-localization of Cy5 signal with macrophages (Iba1). At end of study, livers, kidney and bladder were also collected for ex vivo biodistribution.

[0384] Tumor uptake was greater for the64Cu-HD6-NOTA (also referred to herein as [64Cu]Cu-S08NT3M and D6-OH-3-NOTA-64Cu (32)) than the64Cu-HD5-NOTA (also referred to as [64Cu]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. Higher uptake in tumor of64Cu-HD6-NOTA was observed with higher specific activity compared to lower specific activity at all time points (2H: 5.9 vs 4.5%ID / g, 24H: 15.6 vs 13.6%ID / g, 48H: 14.4 vs 11.8%ID / g for high and low specific activity, respectively). The initial kidney uptake was higher for the high specific activity of64Cu-HD5-NOTA than64Cu-HD6-NOTA due to predominantly renal clearance (64Cu-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). In contrast,64Cu-HD6-NOTA had lower renal clearance with more liver uptake (2H: 13.2%ID / g, 48H: 10.6%ID / g) suggesting biliary clearance. The persistent blood activity of64Cu-HD6-NOTA resulted in accumulation in the tumor over 48 h post-dose (FIG.15). Clearance and biodistribution by PET scan (FIGs 1-18) and ex vivo analyses were consistent with each other and no differences were observed between non-tumor and tumor bearing mice. A portion of the Cy5 signal from the HD6-Cy5 in the tumor was co- localized with macrophages on the tumor perimeter and interior.

[0385] 64Cu-HD6-NOTA is a first in class tumor imaging agent targeting TAMs that exist across many different cancers. Tumor accumulation over time is observed demonstrating uptake and persistence post-dose with a mean tumor uptake of 36.3% and 41.6% ID / g at 24 h and 48 h, respectively. EQUIVALENTS AND SCOPE

[0386] In the claims articles such as “a,” “an,” and “the” may mean one or more than one unless indicated to the contrary or otherwise evident from the context. Claims or descriptions that include “or” between one or more members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context. The present disclosure includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process. 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

[0387] 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. It should it be understood that, in general, where the present disclosure, or aspects of the present disclosure, is / are referred to as comprising particular elements and / or features, certain embodiments of the present disclosure or aspects of the present disclosure consist, or consist essentially of, such elements and / or features. For purposes of simplicity, those embodiments have not been specifically set forth in haec verba herein. It is also noted that the terms “comprising” and “containing” are intended to be open and permits the inclusion of additional elements or steps. Where ranges are given, endpoints are included. Furthermore, unless otherwise indicated or otherwise evident from the context and understanding of one of ordinary skill in the art, values that are expressed as ranges can assume any specific value or sub-range within the stated ranges in different embodiments of the present disclosure, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.

[0388] This application refers to various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. If there is a conflict between any of the incorporated references and the instant specification, the specification shall control. In addition, any particular embodiment of the present disclosure that falls within the prior art may be explicitly excluded from any one or more of the claims. Because such embodiments are deemed to be known to one of ordinary skill in the art, they may be excluded even if the exclusion is not set forth explicitly herein. Any particular embodiment of the present disclosure can be excluded from any claim, for any reason, whether or not related to the existence of prior art.

[0389] Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation many equivalents to the specific embodiments described herein. The scope of the present embodiments described herein is not intended to be limited to the above Description, but rather is as set forth in the appended claims. Those of ordinary skill in the art will appreciate that various changes and modifications to this description may be made without departing from the spirit or scope of the present disclosure, as defined in the following claims. 133 / 156 13813260

Claims

CLAIMS What is claimed is:

1. A dendrimer conjugate of Formula (I′):or a pharmaceutically acceptable salt thereof, wherein: D is a dendrimer; Z is substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted heteroalkylene, or substituted or unsubstituted heteroalkenylene; R1is 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; and p is an integer from 0-20, inclusive.

2. A dendrimer conjugate of Formula (I):or a pharmaceutically acceptable salt thereof, wherein: D is a dendrimer; Z is substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted heteroalkylene, or substituted or unsubstituted heteroalkenylene; R1is 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; and p is an integer from 0-20, inclusive. 134 / 156 138132603. The dendrimer conjugate of claim 1 or 2, wherein Z is substituted or unsubstituted alkylene.

4. The dendrimer conjugate of any one of claims 1-3, wherein Z is substituted or unsubstituted C1-C6 alkylene.

5. The dendrimer conjugate of any one of claims 1-4, wherein Z is substituted or unsubstituted propylene.

6. The dendrimer conjugate of any one of claims 1-5, wherein Z is.

7. The dendrimer conjugate of any one of claims 1-6, wherein q is 0-20.

8. The dendrimer conjugate of any one of claims 1-7, wherein q is 0.

9. The dendrimer conjugate of any one of claims 1-7, wherein q is 1.

10. The dendrimer conjugate of any one of claims 1-9, wherein m is an integer from 52-56, inclusive.

11. The dendrimer conjugate of any one of claims 1-10, wherein m is 54.

12. The dendrimer conjugate of any one of claims 1-11, wherein p is 0, 1, or 2.

13. The dendrimer conjugate of any one of claims 1-12, wherein n is 8, 9, or 10.

14. The dendrimer conjugate of any one of claims 1-13, wherein the dendrimer conjugate is of the formula:, or a pharmaceutically acceptable salt thereof. 135 / 156 1381326015. The dendrimer conjugate of any one of claims 1-6 and 9-13, wherein the dendrimer conjugate is of the formula:, or a pharmaceutically acceptable salt thereof, wherein D is a generation 4 PAMAM dendrimer.

16. The dendrimer conjugate of any one of claims 1-6, wherein the dendrimer conjugate is of the formula:, or a pharmaceutically acceptable salt thereof, wherein p is an integer from 1-10, inclusive, n is an integer from 1-10, inclusive, and D is a generation 4 PAMAM dendrimer.

17. The dendrimer conjugate of any one of claims 1-6, wherein the dendrimer conjugate is of the formula:, or a pharmaceutically acceptable salt thereof, wherein D is a generation 4 PAMAM dendrimer.

18. A dendrimer conjugate of Formula (II′):or a pharmaceutically acceptable salt thereof, wherein: D is a dendrimer; R1is a radionuclide or a chelator of a radionuclide; RAis a reactive moiety comprising a cyclic alkene or cyclic alkyne; 136 / 156 13813260RBis a polycyclic moiety; L1and L2are 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.

19. A dendrimer conjugate of Formula (II):or a pharmaceutically acceptable salt thereof, wherein: D is a dendrimer; R1is a radionuclide or a chelator comprising a radionuclide; RAis a reactive moiety comprising a cyclic alkene or cyclic alkyne; RBis a polycyclic moiety; L1and L2are 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.

20. The dendrimer conjugate of claim 18 or 19, wherein L1and L2are 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.

21. The dendrimer conjugate of any one of claims 18-20, wherein RBis a polycyclic moiety resulting from cycloaddition reaction of the cyclic alkene or cyclic alkyne of RA. 137 / 156 1381326022. The dendrimer conjugate of any one of claims 18-21, wherein RAis: and RB.

23. The dendrimer conjugate of any one of claims 18-22, wherein the dendrimer conjugate is of the formula:, or a pharmaceutically acceptable salt thereof.

24. The dendrimer conjugate of any one of claims 18-23, wherein the dendrimer conjugate is of the formula:, or a pharmaceutically acceptable salt thereof.

25. The dendrimer conjugate of any one of claims 18-24, wherein the dendrimer conjugate is of the formula:, or a pharmaceutically acceptable salt thereof. 138 / 156 1381326026. The dendrimer conjugate of any one of claims 18-25, wherein: 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.

27. The dendrimer conjugate of any one of claims 18-25, wherein: 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.

28. The dendrimer conjugate of any one of claims 18-25, wherein: 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.

29. The dendrimer conjugate of any one of claims 18-25, wherein: m is an integer from 54-63, inclusive; p is an integer from 0-10, inclusive; n is an integer from 2-6, inclusive; and D is a generation 4 PAMAM dendrimer.

30. The dendrimer conjugate of any one of claims 18-25, wherein: 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.

31. The dendrimer conjugate of any one of claims 18-30, wherein the dendrimer conjugate is of the formula: 139 / 156 13813260, or a pharmaceutically acceptable salt thereof.

32. The dendrimer conjugate of any one of claims 18-30, wherein the dendrimer conjugate is of the formula:, or a pharmaceutically acceptable salt thereof.

33. The dendrimer conjugate of any one of claims 18-30, wherein the dendrimer conjugate is of the formula:, or a pharmaceutically acceptable salt thereof.

34. The dendrimer conjugate of any one of claims 17-20, wherein the dendrimer conjugate is of the formula: 140 / 156 13813260, or a pharmaceutically acceptable salt thereof.

35. The dendrimer conjugate of any one of claims 18-30, wherein the dendrimer conjugate is of the formula:, or a pharmaceutically acceptable salt thereof.

36. The dendrimer conjugate of any one of claims 18-30, wherein the dendrimer conjugate is of the formula:, or a pharmaceutically acceptable salt thereof.

37. The dendrimer conjugate of any one of claims 18-30, wherein the dendrimer conjugate is of the formula: 141 / 156 13813260, or a pharmaceutically acceptable salt thereof.

38. The dendrimer conjugate of any one of claims 18-30, wherein the dendrimer conjugate is of the formula:, or a pharmaceutically acceptable salt thereof.

39. The dendrimer conjugate of any one of claims 18-30, wherein the dendrimer conjugate is of the formula:, or a pharmaceutically acceptable salt thereof.

40. The dendrimer conjugate of any one of claims 18-30, wherein the dendrimer conjugate is of the formula: 142 / 156 13813260, or a pharmaceutically acceptable salt thereof.

41. The dendrimer conjugate of any one of claims 18-30, wherein the dendrimer conjugate is of the formula:or a pharmaceutically acceptable salt thereof.

42. The dendrimer conjugate of any one of claims 18-30, wherein the dendrimer conjugate is of the formula:, or a pharmaceutically acceptable salt thereof.

43. The dendrimer conjugate of any one of claims 18-30, wherein the dendrimer conjugate is of the formula: 143 / 156 13813260, or a pharmaceutically acceptable salt thereof.

44. The dendrimer conjugate of any one of claims 18-30, wherein the dendrimer conjugate is of the formula:, or a pharmaceutically acceptable salt thereof.

45. The dendrimer conjugate of any one of claims 18-30, wherein the dendrimer conjugate is of the formula:, or a pharmaceutically acceptable salt thereof.

46. The dendrimer conjugate of any one of claims 18-30, wherein the dendrimer conjugate is of the formula: 144 / 156 13813260, or a pharmaceutically acceptable salt thereof.

47. The dendrimer conjugate of any one of claims 18-30, wherein the dendrimer conjugate is of the formula:, or a pharmaceutically acceptable salt thereof.

48. The dendrimer conjugate of any one of claims 18-30, wherein the dendrimer conjugate is of the formula:, or a pharmaceutically acceptable salt thereof.

49. The dendrimer conjugate of any one of claims 18-30, wherein the dendrimer conjugate is of the formula: 145 / 156 13813260, or a pharmaceutically acceptable salt thereof.

50. The dendrimer conjugate of any one of claims 18-30, wherein the dendrimer conjugate is of the formula:, or a pharmaceutically acceptable salt thereof.

51. The dendrimer conjugate of any one of claims 18-21, wherein RAis:.

52. The dendrimer conjugate of any one of claims 18-21 and 51, wherein the dendrimer conjugate is of the formula: 146 / 156 13813260, or a pharmaceutically acceptable salt thereof.

53. The dendrimer conjugate of any one of claims 18-21 and 51, wherein the dendrimer conjugate is of the formula:, or a pharmaceutically acceptable salt thereof.

54. The dendrimer conjugate of any one of claims 18-21 and 51, wherein the dendrimer conjugate is of the formula:, or a pharmaceutically acceptable salt thereof.

55. The dendrimer conjugate of any one of claims 18-21 and 51, wherein the dendrimer conjugate is of the formula: 147 / 156 13813260, or a pharmaceutically acceptable salt thereof.

56. The dendrimer conjugate of any one of claims 18-21 and 51, wherein the dendrimer conjugate is of the formula:, or a pharmaceutically acceptable salt thereof.

57. The dendrimer conjugate of any one of claims 18-21 and 51, wherein the dendrimer conjugate is of the formula:, or a pharmaceutically acceptable salt thereof.

58. The dendrimer conjugate of any one of claims 18-21 and 51, wherein the dendrimer conjugate is of the formula: 148 / 156 13813260, or a pharmaceutically acceptable salt thereof.

59. The dendrimer conjugate of any one of claims 18-21 and 51, wherein the dendrimer conjugate is of the formula:, or a pharmaceutically acceptable salt thereof.

60. The dendrimer conjugate of any one of claims 18-21 and 51, wherein the dendrimer conjugate is of the formula:, or a pharmaceutically acceptable salt thereof.

61. The dendrimer conjugate of any one of claims 18-21 and 51, wherein the dendrimer conjugate is of the formula: 149 / 156 13813260, or a pharmaceutically acceptable salt thereof.

62. The dendrimer conjugate of any one of claims 31-61, wherein: 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.

63. The dendrimer conjugate of any one of claims 31-61, wherein: 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.

64. The dendrimer conjugate of any one of claims 31-61, wherein: 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.

65. The dendrimer conjugate of any one of claims 31-61, wherein: m is 251; p is 0; n is 5; and D is a generation 6 PAMAM dendrimer. 150 / 156 1381326066. The dendrimer conjugate of any one of claims 1-65, wherein the dendrimer is a polyamidoamine (PAMAM), polypropylamine (POPAM), polyethylenimine, polylysine, polyester, iptycene, aliphatic poly(ether), or an aromatic polyether dendrimer.

67. The dendrimer conjugate of any one of claims 1-66, wherein the dendrimer is a generation 4, generation 5, generation 6, generation 7, or generation 8 PAMAM dendrimer.

68. The dendrimer conjugate of any one of claims 1-67, wherein the dendrimer is a generation 4 PAMAM dendrimer.

69. The dendrimer conjugate of any one of claims 1-67, wherein the dendrimer is a generation 6 PAMAM dendrimer.

70. The dendrimer conjugate of any one of claims 1-69, wherein the radionuclide is selected from the group consisting of18F,44Sc,47Sc,51Cr,51Mn,52Fe,55Co,60Cu,61Cu,62Cu,64Cu,67Cu,67Ga,68Ga,72As,76Br,77Br,82Rb,86Y,88Y,89Sr,89Zr,90Y,94mTc,99mTc,97Ru,103Ru,105Rh,109Pd,110In,111In ,117mSn,123I,124I,125I,131I,133Xe,140La,141Ce,149Pm,149Tb,152Tb,153Sm,161Tb,165Dy,166Dy,166Ho,167Tm,168Yb,175Yb,177Lu,186Re,188Re,198Au,199Au,201Tl,203Pb,211Bi,212Bi,212Pb,213Bi,214Bi,223Ra,225Ac, and227Th or ion thereof.

71. The dendrimer conjugate of any one of claims 1-70, wherein the radionuclide is selected from the group consisting of18F,47Sc,51Cr,51Mn,52Fe,60Cu,62Cu,64Cu,67Cu,67Ga,68Ga,72As,76Br,77Br,88Y,89Zr,90Y,94mTc,99mTc,97Ru,103Ru,105Rh,109Pd,110In,111In ,117mSn,123I,124I,125I,131I,140La,141Ce,149Pm,153Sm,161Tb,165Dy,166Dy,166Ho,167Tm,168Yb,175Yb,177Lu,186Re,188Re,198Au,199Au,203Pb,211Bi,212Bi,213Bi,214Bi, and225Ac, or ion thereof.

72. The dendrimer conjugate of any one of claims 1-71, wherein the radionuclide is18F,64Cu,89Zr,90Y,111In,177Lu,203Pb, or225Ac, or ion thereof.

73. The dendrimer conjugate of any one of claims 1-72, wherein the radionuclide is18F,64Cu, or177Lu, or ion thereof.

74. The dendrimer conjugate of any one of claims 1-73, wherein R1is18F. 151 / 156 1381326075. The dendrimer conjugate of any one of claims 1-73, wherein R1is a chelator of a radionuclide.

76. The dendrimer conjugate of any one of claims 1-73, wherein R1is a chelator comprising a radionuclide.

77. The dendrimer conjugate of claim 75 or 76, wherein the chelator is as shown in FIG. 29B, 78. The dendrimer conjugate of claim any one of claims 75-77, wherein 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).

79. The dendrimer conjugate of any one of claims 75-78, wherein the chelator is DOTA.

80. The dendrimer conjugate of any one of claims 1-78, wherein R1is DOTA chelated to111In.

81. The dendrimer conjugate of any one of claims 1-78, wherein R1is DOTA chelated to90Y.

82. The dendrimer conjugate of any one of claims 75-78, wherein the chelator is NOTA.

83. The dendrimer conjugate of any one of claims 1-78, wherein R1is NOTA chelated to64Cu.

84. A composition comprising the dendrimer conjugate of any one of claims 1-83, or a pharmaceutically acceptable salt thereof.

85. The composition of claim 84, wherein the composition comprises a pharmaceutically acceptable excipient. 152 / 156 1381326086. A method of imaging a tissue in a subject, the method comprising: administering the dendrimer conjugate of any one of claims 1-83, or a pharmaceutically acceptable salt thereof, or the composition of claim 84 or 85 to a subject; and obtaining an image representation of a tissue in the subject.

87. The method of claim 86, wherein the subject has a neurological disorder, an autoimmune disorder, or a cancer.

88. The method of claim 86 or 87, wherein the subject has a neurodegenerative disorder.

89. The method of claim 88, wherein 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.

90. The method of claim 88, wherein the neurodegenerative disorder is relapsing remitting MS, primary progressive MS, or secondary progressive MS.

91. The method of any one of claims 86-90, wherein the tissue in the subject is a tissue of the central nervous system.

92. The method of any one of claims 86-91, further comprising: detecting the dendrimer conjugate in the image representation.

93. The method of claim 92, wherein detection of the dendrimer conjugate in the image representation is indicative of one or more sites of inflammation in the tissue of the subject.

94. The method of claim 93, wherein the one or more sites of inflammation in the tissue of the subject are associated with an inflammatory disease or autoimmune disease.

95. The method of claim 94, wherein the inflammatory disease 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 153 / 156 13813260disease, 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 fibrosis, idiopathic thrombocytopenia purpura, IgA nephropathy, insulin-dependent diabetes, Meniere’s disease, mixed connective tissue disease, multiple sclerosis, myasthenia gravis, pemphigus vulgaris, pernicious anemia, polyarteritis nodosa, polychondritis, polyglandular syndrome, polymyalgia rheumatica, polymyositis and dermatomyositis, primary agammaglobulinemia, primary biliary cirrhosis, psoriasis, Raynaud’s phenomenon, Reiter’s syndrome, rheumatic fever, rheumatoid arthritis, sarcoidosis, scleroderma, Sjogren’s syndrome, stiff-man syndrome, systemic lupus erythematosus, Takayasu arteritis, temporal arteritis, ulcerative colitis, uveitis, vasculitis, vitiligo, and Wegener’s granulomatosis.

96. The method of claim 92 or 93, wherein 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.

97. The method of claim 96, wherein the one or more sites of neuroinflammation in the central nervous system of the subject are associated with a neurodegenerative disorder.

98. The method of claim 97, wherein 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.

99. The method of claim 97, wherein the neurodegenerative disorder is relapsing remitting MS, primary progressive multiple sclerosis, or secondary progressive MS.

100. The method of claim 92, wherein detection of the dendrimer conjugate in the image representation is indicative of one or more cancer cells in the tissue of the subject.

101. The method of claim 100, wherein the one or more cancer cells comprise tumor- associated macrophages. 154 / 156 13813260102. The method of claim 100 or 101, wherein the one or more cancer cells comprise primary tumor cells or metastasized cancer cells.

103. The method of any one of claims 86-102, wherein the image representation is obtained by imaging the subject with a molecular imaging device.

104. The method of claim 103, wherein the molecular imaging device comprises a gamma camera for positron emission tomography (PET) scanning or single photon emission computed tomography (SPECT).

105. A method of treating a cancer in a subject, the method comprising administering the dendrimer conjugate of any one of claims 1-83, or a pharmaceutically acceptable salt thereof, or the composition of claim 84 or 85 to a subject.

106. The method of claim 105, wherein 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.

107. The method of claim 105 or 106, wherein the subject has a primary tumor and / or a metastasized cancer.

108. The method of any one of claims 105-107, wherein the subject has a brain tumor and / or brain metastasis.

109. The method of any one of claims 105-108, wherein the dendrimer conjugate or composition is administered to the subject systemically.

110. The method of any one of claims 105-108, wherein the dendrimer conjugate or composition is administered to the subject intraperitoneally, intravenously, intrathecally, intratumorally, or orally. 155 / 156 13813260

Images