Polyfunctional compounds for use in medical imaging and therapy - Patents.com

Abstract

The present disclosure provides multifunctional compounds for use in medical imaging and therapy, which include two or more of (i) a chelating ligand moiety (CL), (ii) an optical probe moiety (OP), and (iii) a biological targeting moiety (BT).The present disclosure further provides related compositions and methods.The present disclosure provides multifunctional compounds useful in medical imaging and therapy, including pre-, in-situ, and post-surgery medical imaging and therapy.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 63 / 249,180, filed September 28, 2021, the entirety of which is incorporated by reference herein for all purposes.

[0002] FIELD OF THEINVENTION The present invention relates to multifunctional compounds for use in medical imaging and therapy, including radiotherapy and radioimmunotherapy. [Background technology]

[0003] background The current standard of care in medical imaging utilizes single agents for each of PET imaging, gadolinium-enhanced imaging (cMRI), optical / fluorescent imaging, and additional separate molecules for radioisotope therapy (RIT, or "radiotherapy"). In some cases, mixtures of several different molecules may be used, for example, combinations of PET / optical, optical / RIT, or PET / RIT agents.

[0004] With imaging agents as single agents, e.g., PET-only, optical-only, or RIT-only imaging agents, empirical imaging is not possible. Instead, each of the different molecules distributes differently in the patient, which often results in different signals from different and conflicting anatomical locations in the patient. For example, if multiple imaging agents are administered to a patient along with RIT agents, e.g., a mixture of stand-alone PET / FL / RIT agents, the lesions may present as fluorescence and / or alpha / beta particle emission, but not on a PET scan, since the different agents distribute differently, e.g., due to differences in blood clearance, nonspecific tissue accumulation, ligand affinity, and receptor saturation. This leaves it up to the surgeon / radiation oncologist / radiologist to reconcile the signal differences. Such conflicting information from multiple single imaging agents is highly problematic in the operating room, where there is limited time to resolve the conflicts, and treatment may be compromised by the lack of coherent imaging information. For example, treatment may be compromised if tumor margins are fluorescent but cannot be demonstrated on a PET scan, or conversely, if a spot on the PET scan does not fluoresce in the operating room.

[0005] Mixtures of imaging agents targeting the same ligand also suffer from the problem of weaker signals. This problem can be illustrated by two scenarios: 1) Assume a patient with a net million PSMA ligand binding sites is treated with a mixture of a PSMA-specific PET agent and a PSMA-specific RIT agent. If 50% of the ligand binding sites bind to the PET agent and 50% of the sites bind to the RIT agent, then the PSMA-positive tumor will receive only 50% of the theoretical maximum of maximum contrast with PET, or 50% of the maximum RIT dose due to blocking of the ligand binding sites by the PET molecules. 2) In the second scenario, the patient is first imaged with a PSMA-specific PET agent and then treated at a later time with a subsequent PSMA-specific RIT agent. If the ligand binding sites are saturated in imaging via the PET agent (100% of the sites are bound), the subsequently injected RIT dose will be ineffective or less effective due to the PET agent blocking available binding sites before the introduction of the RIT dose. Summary of the Invention [Means for solving the problem]

[0006] Summary of the Disclosure The present invention addresses problems associated with single agent imaging agents and mixtures of single agent imaging agents with each other or with RIT agents by providing single molecule agents that contain multiple functional modalities, e.g., fluorophores, PET agents, RIT agents, and optionally biological targeting agents, such that single molecules as described herein are suitable for performing optical fluorescence, PET imaging, and RIT imaging. The multifunctional compounds of the present invention necessarily provide superior signal-to-noise (S / N) ratios and / or radioisotope loadings compared to mixtures of single agents with the same set of functionalities. In addition, the multifunctional compounds described herein facilitate the synthesis and testing of single molecules (e.g., single molecular species with the same total atomic number, elemental connectivity, 1H-NMR characterization) simplifies the FDA New Drug Application (NDA) process compared to applications for multiple separate molecules, thus providing advantages in terms of increased efficiency for synthesis and regulatory approval. Additionally, the multifunctional compounds described herein provide advantages in terms of increased efficiency for synthesis and regulatory approval compared to mixtures of single agents.

[0007] In addition, the multifunctional compounds described herein provide molecularly coherent PET and fluorescence images that are advantageous for image-guided surgery, including robotic and robot-assisted surgery. In some embodiments, the present disclosure further provides a surgical system for image-guided surgery, including an in-surgery PET scanner (e.g., PET / CT or PET / MRI) with a fluorescence endoscope or camera, for example, located on the surgical robot or on a histopathology cart on the back table. The surgical system provides demonstrative PET and fluorescence imaging during surgery, thereby improving patient treatment.

[0008] The present disclosure provides multifunctional compounds useful in medical imaging and therapy, including pre-surgical, in situ, and post-surgical medical imaging and therapy.

[0009] Provided are compounds comprising three functional moieties: (i) a chelating ligand moiety (CL), (ii) an optical probe moiety (OP), and (iii) a biological targeting moiety (BT), or pharma- ceutically acceptable salts thereof, related compositions, and methods of use.

[0010] In one aspect, the compound is (i) a chelating ligand moiety (CL), (ii) an optical probe portion (OP); and (iii) Biological targeting moiety (BT) Includes.

[0011] Each of moieties (i)-(iii) may include one or more linkers (e.g., L 1 , L 2 , L3 , L 4 , L 5 , L 6 and L 7 ) to at least one other moiety to form a compound of formula X. Also provided are, inter alia, compounds that include four functional moieties: (i) a fluorine atom-bearing moiety (FCM), (ii) a chelating ligand moiety (CL), (iii) an optical probe moiety (OP), and (iv) a biological targeting moiety (BT), related compositions, and methods of use.

[0012] In one aspect, the compound is (i) a fluorine atom-bearing moiety (FCM); (ii) a chelating ligand moiety (CL); (iii) an optical probe portion (OP); and (iv) Biological targeting moiety (BT) each of moieties (i)-(iv) comprises one or more linkers disclosed herein (e.g., L 1 , L 2 , L 3 , L 4 , L 5 , L 6 and L 7 ) to at least one other moiety to form a compound of formula I.

[0013] In some embodiments, the compound has the structure of formula (I): [ka] has.

[0014] In some embodiments, the compound has the structure of formula (Ia): [ka] has.

[0015] In some embodiments, the compound has the structure of formula (II) [ka] has.

[0016] In some embodiments, the compound has the structure of formula (III) [ka] has.

[0017] In some embodiments, the compound has the structure of formula (IV-a) or (IV-b) [ka] has.

[0018] In some embodiments, the compound has the structure of formula (Va) or (Vb): [ka] has.

[0019] In some embodiments, the compound has the structure of formula (VI-a) or (VI-b) [ka] has.

[0020] In one aspect, there is provided a composition or pharmaceutical composition comprising a compound of Formula (I), (Ia), (Ia-1), (II), (III), (IV-a), (IV-b), (Va), (Vb), (VI-a), (VI-b), (X), (Xa), (XI), (XII), (XIII-a), (XIII-b), (XIV-a) or (XIV-b), or a pharma- ceutically acceptable salt thereof, or a subembodiment as described herein.

[0021] In one aspect, there is provided a kit comprising a compound of Formula (I), (Ia), (Ia-1), (II), (III), (IV-a), (IV-b), (Va), (Vb), (VI-a), (VI-b), (X), (Xa), (XI), (XII), (XIII-a), (XIII-b), (XIV-a) or (XIV-b), or a pharma- ceutically acceptable salt thereof, or any subembodiment described herein, in solid powder form, and a solid phase extraction device suitable for adsorbing a labeled analyte, and optionally further comprising one or more sterilizing solutions selected from purification, elution, washing, and neutralization solutions.

[0022] In one aspect, a method for medical imaging in a subject is provided. The method includes (i) administering to a subject a compound of Formula (I), (Ia), (Ia-1), (II), (III), (IV-a), (IV-b), (Va), (Vb), (VI-a), (VI-b), (X), (Xa), (XI), (XII), (XIII-a), (XIII-b), (XIV-a) or (XIV-b), or a pharma- ceutically acceptable salt thereof, or any subembodiment described herein, or a pharmaceutical composition comprising same; and ii) performing medical imaging of the subject's internal biological tissue using a technique selected from at least one or two of positron emission tomography (PET), single photon emission computed tomography (SPECT), magnetic resonance imaging (MRI), contrast aided (e.g., gadolinium contrast) magnetic resonance imaging (cMRI), and fluorescence (FL) or absorbance-based optical imaging.

[0023] In one aspect, a method is provided for treating cancer in a subject using radioisotope therapy, the method comprising administering to the subject a compound of formula (I), (Ia), (Ia-1), (II), (III), (IV-a), (IV-b), (Va), (Vb), (VI-a), (VI-b), (X), (Xa), (XI), (XII), (XIII-a), (XIII-b), (XIV-a) or (XIV-b), or a pharma- ceutically acceptable salt thereof, or a subembodiment described herein, or a pharmaceutical composition comprising same, wherein the compound comprises a radioisotope suitable for radioisotope therapy.

[0024] In one aspect, the CL portion of the compound comprises a radiometal suitable for radioisotope therapy, and the method further comprises treating the subject with radioisotope therapy using administration of a single compound of Formula (I), (Ia), (Ia-1), (II), (III), (IV-a), (IV-b), (Va), (Vb), (VI-a), (VI-b), (X), (Xa), (XI), (XII), (XIII-a), (XIII-b), (XIV-a) or (XIV-b), or a pharma- ceutically acceptable salt thereof, or a subembodiment described herein, such that imaging and radiotherapy are performed simultaneously.

[0025] In one embodiment, the CL portion of the compound comprises a metal suitable for contrast-assisted (eg, gadolinium contrast) magnetic resonance (cMRI) or contrast-enhanced computed tomography imaging.

[0026] In one embodiment, the biological targeting moiety is selected from a blood cell (e.g., a red blood cell (RBD), a white blood cell (WBC), or a platelet), a peptide, a small molecule, a prodrug, a nucleic acid (e.g., DNA, or RNA), an aptamer, an oligosaccharide, and an antibody or antigen-binding fragment thereof.

[0027] In one embodiment, the BT portion of the compound further comprises a drug or prodrug, and the method optionally further comprises treatment with the drug or prodrug. [Brief description of the drawings]

[0028] [Figure 1] 1A-1C: Exemplary arrangements of moieties in an imaging agent including (i) a fluorine atom-bearing moiety (FCM), (ii) a chelating ligand moiety (CL), (iii) an optical probe moiety (OP), and (iv) a biological targeting moiety (BT).

[0029] [Diagram 2] 2A-2B: A, scheme for attaching a biological targeting moiety (BT) via a reactive cross-linking group. B, exemplary compounds of formula I. Box 1 represents the FCM, box 2 represents the CL, and box 3 represents the OP.

[0030] [Figure 3-1] 3A-3C show exemplary synthesis reactions described in Example 1. [Figure 3-2] Same as above.

[0031] [Figure 4] FIG. 4 shows exemplary biological targeting moieties (BT). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0032] Detailed Description Provided are compounds of Formula (I), (Ia), (Ia-1), (II), (III), (IV-a), (IV-b), (Va), (Vb), (VI-a), (VI-b), (X), (Xa), (XI), (XII), (XIII-a), (XIII-b), (XIV-a) or (XIV-b), or pharma- ceutically acceptable salts thereof, or subembodiments described herein, compositions comprising same, and methods of use in PET imaging, optical / fluorescence imaging including gadolinium contrast imaging (cMRI) and metal complex applications, and medical imaging and therapy including radioisotope therapy (RIT) and radioimmunotherapy.

[0033] In one embodiment, the compound comprises at least i) a chelating ligand moiety (CL), ii) an optical probe moiety (OP), iii) a biological targeting moiety (BT), and iv) a fluorine atom-bearing moiety (FCM), the FCM comprising one or more fluorine atoms, as well as fluorine-18 ( 18 F) (preferably when the compound is utilized for PET imaging) and Fluorine-19 ( 19 F).

[0034] In some embodiments, the chelating ligand moiety (CL) can bind to a metal ion or metal that can be used in PET imaging, radioisotope therapy, or MRI contrast imaging. Examples of such metals include lutetium (Lu, e.g., 175 Lu or 177 Lu), actinium (Ac, e.g. 217 Ac, 225 Ac), gallium (Ga, e.g. 67 Ga, or 68 In some embodiments, the metal may be selected from the group consisting of arsenic (Ar), copper (Cu), samarium (Sm), radium (Ra), yttrium (Y), palladium (Pd), iridium (Ir), gadolinium (Gd), or lead (Pb). 125 I and 64 Cu may be complexed with a compound for PET imaging. In some embodiments, 90 Y may be complexed with a compound for SPECT imaging. In some embodiments, gadolinium (Gd) is a stable isotope (i.e., a non-radioactive nuclide) for imaging (MRI imaging).

[0035] In some embodiments, atomic isotope substitutions, e.g. 19 Instead of F 18 F, 177 Instead of Lu 175 Lu can be made. These substitutions do not change the sum of all of the atomic numbers of the atoms in the molecule / compound, but they do change the atomic weights.

[0036] In some embodiments, the fluorine atom-containing moiety (FCM) includes, but is not limited to, a fluorine captor. In some embodiments, the FCM moiety allows visualization of the tissue of interest by PET imaging. In some embodiments, the moiety contains either two or more fluorine atoms, which are: 18 F or 19 Either F (" 18 / 19 In certain embodiments, the FCM can be 18 The FCM comprises a fluorine atom-bearing moiety that can optionally function as a PET contrast agent by virtue of the inclusion of F. In certain embodiments, the FCM is not a PET contrast agent. 19 It includes a fluorine atom-bearing moiety that may contain F.

[0037] for example, 18 F-fluorophore-R molecules, for example, combine a fluorophore with an R reactive group and a labile fluorine-containing group (e.g., -CRF, -BF ; '' or -SiF3) to 19 Generate the F-fluorophore-R molecule and then 19 The F-fluorophore-R molecule is 18 F 19 Under conditions where it isotopically exchanged with F atoms (e.g., acidic pH, e.g., 2.5), aqueous H[ 18 F], thereby forming at least one 18 F can be prepared by obtaining F. The isotope exchange method is described, for example, in U.S. Pat. No. 8,114,381, the contents of which are incorporated herein by reference.

[0038] In some embodiments, the optical probe moiety (OP) may comprise any type of molecule suitable for fluorescence or optical contrast (absorbance) imaging. In some embodiments, the optical probe comprises a fluorophore or other highly photon absorbing agent, such as indocyanine green, tri-, penta- or heptamethine cyanine, fluorescein, rhodamine, or Evans Blue dye.

[0039] As used herein, the term "fluorophore" (or "fluorescent species") refers to a compound that has fluorescent properties when appropriately stimulated by electromagnetic radiation. Fluorophores contemplated herein can absorb and emit light of any suitable wavelength. In some embodiments, it may be desirable to select a fluorophore that has specific absorption and emission characteristics. For example, in different embodiments, a fluorophore may be 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 510, 520, 530, 540, 550, 560, 570, 580, 590, 600, 610, 620, 630, 640, 650, 660, 670, 680, 690, 700, 710, 720, 730, 740, 750, 760, 770, 780, 790, 800, 810, 820, 830, 840, 850, 860, 870, 880, 890, 900, 910, 920, 930, 940, 950, 960, 970, 980, 990, 1000, 1010, 1020, 10 , 540, 550, 560, 570, 580, 590, 600, 610, 620, 630, 640, 650, 660, 670, 680, 690, 700, 710, 720, 730, 740, 750, 760, 770, 780, 790 or 800 nm, or within a range bounded by any two of the above values. In certain embodiments, the fluorophore emits at any of the above wavelengths, or within a range bounded by any two of the above values, where it is understood that the fluorophore generally emits at a longer wavelength than the absorbed wavelength. The impinging electromagnetic radiation (i.e., absorbed by the fluorophore) may be in a dispersed form, or alternatively in a focused form, such as a laser. Furthermore, the radiation absorbed or emitted can be, for example, in the form of far infrared, infrared, far red, visible, near ultraviolet, or ultraviolet.

[0040] The fluorophore considered herein is an organic fluorophore, which generally contains at least one carbon-carbon bond and at least one carbon-hydrogen bond.In different embodiments, the organic fluorophore can include, for example, charged (i.e., ionic) molecules (e.g., sulfonate or ammonium groups), uncharged (i.e., neutral) molecules, saturated molecules, unsaturated molecules, cyclic molecules, bicyclic molecules, tricyclic molecules, polycyclic molecules, acyclic molecules, aromatic molecules, and / or heterocyclic molecules (i.e., by substituting the ring with one or more heteroatoms selected from, for example, nitrogen, oxygen, and sulfur).In the particular case of unsaturated fluorophores, the fluorophore contains one, two, three, or more carbon-carbon and / or carbon-nitrogen double and / or triple bonds. In a particular embodiment, the fluorophore contains at least two (e.g., two, three, four, five, or more) conjugated double bonds (i.e., polyene linkers), apart from any aromatic groups that may be present in the fluorophore. In some embodiments, the fluorophore is a fused polycyclic aromatic hydrocarbon (PAH) containing at least two, three, four, five, or six rings (e.g., naphthalene, pyrene, anthracene, chrysene, triphenylene, tetracene, azulene, and phenanthrene), where the PAH may be optionally ring substituted or derivatized with one, two, three, or more heteroatoms or heteroatom-containing groups. In some embodiments, the fluorophore contains a polyalkylene oxide group containing at least two, three, or four alkylene oxide units. In some embodiments, the fluorophore contains at least one sulfonic acid or sulfonate group.

[0041] In some embodiments, the organic fluorophore is a xanthene derivative (e.g., fluorescein, rhodamine, Oregon Green, eosin, and Texas Red), a cyanine or a derivative or subclass thereof (e.g., streptocyanin, hemicyanin, closed cyanin, phycocyanin, allophycocyanin, indocarbocyanine, oxacarbocyanine, thiacarbocyanine, merocyanine, and phthalocyanine), a naphthalene derivative (e.g., dansyl and prodan derivatives), a coumarin and its derivatives, an oxadiazole and its derivatives (e.g., pyridyloxazole, nitrobenzoxadiazole, and benzoxadiazole), a pyrene and its derivatives, an oxazine and its derivatives (e.g., Nile Red, Nile Blue, and Cresyl Violet), an acridine derivative (e.g., proflavine, acridine orange, and acridine yellow), an arylmethine derivative (e.g., auramine, crystal violet, and malachite green), and a tetrapyrrole derivative (e.g., porphyrin and bilirubin).

[0042] In some embodiments, the fluorophore has the formula: [ka] where n is an integer from 0 to 12. Other structures related to or derived from formula (1) are also contemplated herein, as fully described in Guieu, V., et al., Eur. J. Org. Chem., 2007, 804-810, which is incorporated herein by reference in its entirety.

[0043] In some embodiments, the fluorophore has the formula: [ka] The moiety of formula (2) is as defined above. The circular arc of formula (2) indicates a nitrogen-containing ring, such as pyrrolyl. Alternatively, the circular arc may represent a bicyclic ring system, such as a benzopyrrolyl fused ring system. Other structures related to or derived from formula (2) are also contemplated herein, as fully described in Stathatos, E., et al. Chem. Mater., 2001, 13, 3888-3892, and Yao, Q.-H., et al. J. Mater. Chem., 2003, 13, 1048 1053, which are incorporated herein by reference in their entirety.

[0044] In some embodiments, the fluorophore comprises a cyanine dye (i.e., a cyanine-based fluorophore). The term "cyanine dye," as used herein, refers to any of the dyes known in the art that contain two indolyl or benzoxazole ring systems interconnected by a conjugated polyene linker. Cyanine dyes typically contain at least two or three conjugated carbon-carbon double bonds, at least one of which is not present in the ring depicted, for example, in any of formulas (1)-(3). Cyanine dyes (or other types of dyes) often contain at least two pyrrolyl rings. Some specific examples of cyanine dyes are Cy *The family of dyes includes, for example, Cy2, Cy3, Cy3B, Cy3.5, Cy5, Cy5.5, Cy7, and Cy9. The term "cyanine moiety" as used herein generally includes bis-indolyl-polyene or bis-benzoxazolyl-polyene systems, but excludes groups attached to the ring nitrogen atoms in the indolyl or benzoxazolyl groups. Cyanine dyes include the Alexa® family of dyes (e.g., Alexa Fluor 350, 405, 430, 488, 500, 514, 532, 546, 555, 568, 594, 610, 633, 647, 660, 700, 750, and 790), the ATTO® family of dyes (e.g., ATTO 390, 425, 465, 488, 495, 520, 532, 550, 565, 590, 594, 601, 615, 619, 629, 635, 645, 663, 680, 700, 729, and 740), and the Dye family of dyes (e.g., DY 530, 547, 548, 549, 550, 554, 556, 560, 590, 610, 615, 630, 631, 631, 632, 633, 634, 635, 636, 647, 648, 649, 650, 651, 652, 675, 676, 677, 680, 700, 701, 730, 731, 732, 734, 750, 751, 752, 776, 780, 781, 782, and 831). ATTO dyes can have several structural motifs, including coumarin-based, rhodamine-based, carbopyronin-based, and oxazine-based structural motifs, among others.

[0045] In some embodiments, the fluorophore allows visualization of the tissue of interest, for example, by fluorescent imaging and "optical" imaging (e.g., visual observation with the naked eye). Fluorophores include, for example, Cy3, Cy7, fluorescein, and any of the fluorophores known in the art, such as those described above. In some embodiments, the fluorophore is preferably a cyanine fluorophore, more particularly a hydrophilic cyanine fluorophore.

[0046] In some embodiments, the biological targeting moiety (BT) is selected from a blood cell (e.g., a red blood cell (RBD), a white blood cell (WBC), or a platelet), a peptide, a small molecule, a prodrug, a nucleic acid (e.g., a DNA, or an RNA molecule), an aptamer, an oligosaccharide, and an antibody or antigen-binding fragment thereof.

[0047] In some embodiments, the BT is an agent that specifically binds to a biological molecule, such as a cell surface receptor or ligand. In some embodiments, the BT is a PSMA inhibitor, such as 2-(3-((S)-5-amino-1-carboxypentyl)ureido)pentanedioic acid; a fibroblast activation protein (FAP) inhibitor, such as 6-butoxy-N-(2-(2-cyanopyrrolidin-1-yl)-2-oxoethyl)quinoline-4-carboxamide or 6-butoxy-N-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)quinoline-4-carboxamide; an arginine-glycine-glutamic acid fibronectin inhibitor, such as ... tin or integrin binding peptides, such as 2-(5-benzyl-11-(3-guanidinopropyl)-8-methyl-3,6,9,12,15-pentaoxo-1,4,7,10,13-pentaazacyclopentadecan-2-yl)acetic acid (RGD); somatostatin binding peptides, such as 2-(13-((1H-indol-3-yl)methyl)-10-(4-aminobutyl)-16-(4-hydroxybenzyl)-7-(1-hydroxyethyl)-6,9,12,15,18-pentaoxo-19-(3-phenyl-2- propionamidopropanamido)-1,2-dithia-5,8,11,14,17-pentaazacycloicosane-4-carboxamido)-3-hydroxybutanoic acid (TATE) or 13-((1H-indol-3-yl)methyl)-10-(4-aminobutyl)-N-(1,3-dihydroxybutan-2-yl)-16-(4-hydroxybenzyl)-7-(1-hydroxyethyl)-6,9,12,15,18-pentaoxo-19-(3-phenyl-2-propionamidopropanamido)-1,2-dithia-5, 8,11,14,17-pentaazacycloicosane-4-carboxamide (TOC); pentixafor chemokine receptor binding agents, such as 1-(3-((2S,5S,11R,14R)-11-(4-hydroxybenzyl)-13-methyl-14-(3-(methylamino)propyl)-5-(naphthalen-2-ylmethyl)-3,6,9,12,15-pentaoxo-1,4,7,10,13-pentaazacyclopentadecan-2-yl)propyl)guanidine or related variants.

[0048] In some embodiments, the BT is an antibody or an antigen-binding fragment thereof. In some embodiments, the antibody may consist of an immunoglobulin (Ig) molecule, such as an IgG molecule. In some embodiments, the antibody may be an antigen-binding fragment of an Ig molecule, such as an F(ab')2 or Fab' fragment, or a single chain Fv fragment (scFv). In some embodiments, the antibody or antigen-binding fragment thereof may be a humanized antibody. In some embodiments, the antibody or antigen-binding fragment thereof is a humanized single chain heavy chain antibody (HcAb) consisting of two heavy chains (variable heavy chain homodimer, VHH) linked to an antigen-binding variable domain. In some embodiments, the HcAb may be derived from a camelid, such as a camel or llama, or a cartilaginous fish (Chondrichthyes), such as a shark.

[0049] In some embodiments, the BT is an antibody or an antigen-binding fragment thereof that binds directly to a molecule displayed on the cell surface of the target cancer cell or intracellularly within the target cancer cell. In some embodiments, the BT is an antibody or an antigen-binding fragment thereof selected from Herceptin, Annexin, and Erbitux.

[0050] In some embodiments, the molecule targeted for binding by the BT is selected from PD-L1, HER2 / neu (erbB-2, CD340, a receptor tyrosine kinase also called proto-oncogene Neu, Erbb2, or ERBB2, primarily associated with breast cancer), epidermal growth factor receptor (EGFR, found in multiple cancers), fibroblast activation protein (FAP, found in multiple cancers), CXC chemokine receptor (CXCR, found in multiple cancers), somatostatin receptor 2 (SSTR2, found primarily in endocrine tissue-derived cancers including neuroendocrine cancers, e.g., small cell lung cancer or SCLC), and epithelial cell adhesion molecule (EPCAM, found in multiple cancers).

[0051] In some embodiments, the biological targeting moiety (BT) is a radiolabeled antibody or antigen-binding fragment thereof suitable for radioimmunotherapy. Suitable radionuclides for radioimmunotherapy include beta emitters, e.g. 90 yttrium, 131 Iodine, 177 lutetium, 188 Rhenium and 67 Copper, an alpha emitter, e.g. 213 Bismuth ( 213 Bisumth), 211 Astatine and 225 Actinium, as well as Auger electron emitters, e.g. 125 Contains iodine.

[0052] In some embodiments, the biological targeting moiety (BT) is a protein or peptide, such as an annexin, engineered to bind to a specific biological molecule, such as programmed cell death ligand 1 (PD-L1).

[0053] In some embodiments, the biological targeting moiety (BT) is selected from somatostatin, the SSR agonist tyrosine-octreotate (TATE), and the SSTR2 targeting moiety, TOC, each of which is suitable for binding to SSTR2.

[0054] In some embodiments, the biological targeting moiety (BT) is pentixafor, which is suitable, for example, for chemokines that target CXCR4.

[0055] In some embodiments, the biological targeting moiety (BT) is a nucleic acid-based molecule, such as pegaptanib sodium / Macugen (VEGF targeting), E10030 (PDGF), ARC1905 (C5), AS1411 (nucleolin), NOX-A12 (CXCL12), NOX-E36 (CCL2), NOX-H94 (hepcidin), ARC1779 (vWF), NU172 (FIXa), BX499 (TFPI).

[0056] In some embodiments, the biological targeting moiety (BT) can be a prodrug or a derivative thereof, such as acyclovir, fluorouracil, cyclophosphamide, diethylstilbenstrol, DOPA, mercaptopurine, mitomycin, zidovudine, carbamazepine, captopril, carisoprodol, heroin, molsidomine, leflunomide, paliperidone, phenacetin, primidone, psilocybin, sulindac, fursultiamine, codeine loperamide oxide, oxyphenisatin, sulfasalazine, acetylsalicylate, bacampicillin, bambuterol, chloramphenicol succinate, dipivefrin, fosphenytoin, lisdexamfetamine, pralidoxime, ADEPT, GDEPT, VDEPT. In some embodiments, the BT moiety comprises a prodrug that readily undergoes chemical change under physiological conditions to provide a therapeutically effective chemical reagent (e.g., an inhibitor, agonist, modulator, or regulator). In some embodiments, prodrugs of the compounds described herein may be converted in vivo after administration, or may be converted to a therapeutically effective chemical reagent by chemical or biochemical methods in an ex vivo environment, such as when contacted with a suitable enzyme or chemical reagent.

[0057] In some embodiments, the biological targeting moiety (BT) is an oligosaccharide, such as chitosan oligosaccharide (anti-inflammatory, antibacterial activity), fibrinogen oligosaccharide (blood clotting, venous tromboembolism).

[0058] In some embodiments, the biological targeting moiety (BT) is a cell, particularly a blood cell, such as a red blood cell or a platelet. Methods for binding cells to the compounds described herein are provided below in the discussion of reactive crosslinking groups.

[0059] In some embodiments, the biological targeting moiety (BT) is attached to other moieties using the scheme shown in FIG. 2A. The "R" group represents a reactive crosslinking group capable of binding to blood cells. Exemplary reactive crosslinking groups include amino-reactive groups, carboxy-reactive groups, thiol-reactive groups, alcohol-reactive groups, phenol-reactive groups, aldehyde-reactive groups, and ketone-reactive groups. Amino-reactive groups can include carboxy groups (-COOR', where R' is H or a hydrocarbon group), activated ester groups (-COOR', where R' is a carboxy-activating group, such as deprotonated N-hydroxysuccinimide, i.e., NHS), carbodiimide ester groups (e.g., EDC), tetrafluorophenyl esters, dichlorophenol esters, epoxy (e.g., glycidyl) groups, isothiocyanates, sulfonyl chlorides, dichlorotriazines, aryl halides, and azides, as well as sulfo derivatives thereof, and combinations thereof. Carboxy-reactive groups can include amino and hydroxyalkyl groups, typically in the presence of a carboxy-activating agent to form an activated ester. Some examples of thiol-reactive groups include maleimide ("Mal") groups, haloacetamide (e.g., iodoacetamide) groups, disulfide groups, thiosulfate, and acryloyl groups. Alcohol- and phenol-reactive groups can include aldehyde, ketone, haloalkyl, isocyanate, and epoxy (e.g., glycidyl) groups. Aldehyde- and ketone-reactive groups can include phenol, hydrazide, semicarbazide, carbohydrazide, and hydroxylamine groups. Other reactive groups include 6-oxyguanine and phosphoramidite groups. The term "reactive group" can further encompass any larger group (e.g., a hydrocarbon group, such as a cyclic or aromatic hydrocarbon) to which a reactive crosslinking group is attached. For example, a 6-oxyguanine group can include a ring-containing linking moiety attached to the 6-oxy atom for attachment to a linking portion.In other embodiments, the reactive group may be derivatized, such as by including any of the aforementioned hydrophilic groups, such as a sulfonate (eg, a sulfo-NHS group), a carboxy, a hydroxy, or a halide group. compound

[0060] The abbreviations used herein have their conventional meaning within the chemical and biological arts (chemical biology). The chemical structures and formulas set forth herein are constructed according to the standard rules of chemical valency known in the chemical arts.

[0061] Where substituents are specified by their conventional chemical formula written from left to right, they equally encompass the chemically identical substituents that would result from writing the structure from right to left, e.g., -CH2O- is equivalent to -OCH2-.

[0062] The term "alkyl," by itself or as part of another substituent, means, unless otherwise stated, a straight-chain (i.e., unbranched) or branched carbon chain (or carbons), or combinations thereof, which may be fully saturated, monounsaturated, or polyunsaturated, and which can include monovalent, divalent, and polyvalent radicals. An alkyl can be any number of carbons, e.g., C 1~2 , C 1~3 , C 1~4 , C 1~5 , C 1~6 , C 1~7 , C 1~8 , C 1~9 , C 1~10 , C 2~3 , C 2~4 , C 2~5 , C 2~6 , C 3~4 , C 3~5 , C 3~6 , C 4~5 , C 4~6 and C 5~6An alkyl group can be a non-cyclized chain. Examples of saturated hydrocarbon radicals include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, methyl, homologs and isomers of, e.g., n-pentyl, n-hexyl, n-heptyl, n-octyl, etc.

[0063] As used herein, the term "alkylene" refers to a straight-chain or branched saturated aliphatic radical, i.e., a divalent hydrocarbon radical, having a specified number of carbon atoms and linking at least two other groups. The two moieties linked to the alkylene can be linked to the same atom or different atoms of the alkylene group. For example, a straight-chain alkylene can be a divalent radical of -(CH2)n-, where n is 1, 2, 3, 4, 5, or 6. Representative alkylene groups include, but are not limited to, methylene, ethylene, propylene, isopropylene, butylene, isobutylene, sec-butylene, pentylene, and hexylene. The alkylene group can be substituted or unsubstituted. In some embodiments, the alkylene group is substituted with 1 to 2 substituents. By way of non-limiting example, suitable substituents include halogen and hydroxyl.

[0064] The term "heteroalkyl", alone or in combination with another term, means, unless otherwise stated, a stable straight or branched chain containing at least one carbon atom and at least one heteroatom (e.g., O, N, P, Si, and S), or a combination thereof, where the nitrogen and sulfur atoms can be optionally oxidized and the nitrogen heteroatom can be optionally quaternized. The heteroatom(s) (e.g., O, N, S, Si, or P) can be placed at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule. Heteroalkyl is a non-cyclized chain. Examples include, but are not limited to, -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-S-CH2, -S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH=CH-O-CH3, -Si(CH3)3, -CH2-CH=N-OCH3, -CH=CH-N(CH3)-CH3, -O-CH3, -O-CH2-CH3, and -CN. Up to two or three heteroatoms may be consecutive, such as, for example, -CH2-NH-OCH3 and -CH2-O-Si(CH3)3. The heteroalkyl moiety may contain one heteroatom (e.g., O, N, S, Si, or P). A heteroalkyl moiety may optionally contain two different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may optionally contain three different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may optionally contain four different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may optionally contain five different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may optionally contain up to eight different heteroatoms (e.g., O, N, S, Si, or P).

[0065] Similarly, the term "heteroalkylene," by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from heteroalkyl, as exemplified, but not limited to, by -CH-CH-S-CH-CH- and -CH-S-CH-CH-NH-CH-. For heteroalkylene groups, heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, etc.). Still further, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied by the direction in which the formula of the linking group is written. For example, the formula -C(O)R'- represents both -C(O)R'- and -R'C(O)-. As stated above, heteroalkyl groups, as used herein, include groups that are attached to the remainder of the molecule via a heteroatom, e.g., -C(O)R', -C(O)NR', ​​-NR'R'', -OR', -SR', and / or -SOR'. When "heteroalkyl" is described followed by a specific heteroalkyl group, e.g., -NR'R'', it will be understood that the terms heteroalkyl and -NR'R'' are not overlapping and are not mutually exclusive. Rather, the specific heteroalkyl group is described to add clarity. Thus, the term "heteroalkyl" should not be construed herein as excluding specific heteroalkyl groups, e.g., -NR'R'', etc.

[0066] The terms "cycloalkyl" and "heterocycloalkyl", alone or in combination with other terms, refer to cyclic versions of "alkyl" and "heteroalkyl", respectively, unless otherwise stated. Cycloalkyl and heterocycloalkyl are not aromatic. Additionally, for heterocycloalkyl, a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. Examples of heterocycloalkyl include, but are not limited to, 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl, and the like. A "cycloalkylene" and a "heterocycloalkylene," alone or as part of another substituent, mean a divalent radical derived from a cycloalkyl and heterocycloalkyl, respectively.

[0067] As used herein, "cycloalkyl" refers to a saturated ring assembly containing 3 to 10 ring atoms, or the specified number of atoms. Cycloalkyl can be any number of carbons, e.g., C 3~6 , C 4~6 , C 5~6 , C 3~8 , C 4~8 , C 5~8 , C 6~8The cycloalkyl ring may be saturated or unsaturated, where the unsaturated cycloalkyl ring may have one or two double bonds. Cycloalkyl rings include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl. The cycloalkyl group may be substituted or unsubstituted. In some embodiments, the term "cycloalkyl" refers to a monocyclic, bicyclic, or polycyclic cycloalkyl ring system. In some embodiments, a monocyclic ring system is a cyclic hydrocarbon group containing 3 to 8 carbon atoms, such groups may be saturated or unsaturated, but are not aromatic. In some embodiments, a cycloalkyl group is fully saturated. Examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. A bicyclic cycloalkyl ring system is a bridged monocyclic ring or a fused bicyclic ring. In some embodiments, a bridged monocyclic ring contains a monocyclic cycloalkyl ring in which two non-adjacent carbon atoms of the monocyclic ring are linked by an alkylene bridge of between 1 and 3 additional carbon atoms (i.e., a bridging group of the form (CH)w, where w is 1, 2, or 3). Representative examples of bicyclic ring systems include, but are not limited to, bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane, and bicyclo[4.2.1]nonane.

[0068] In some embodiments, heterocycloalkyl is heterocyclyl. As used herein, the term "heterocyclyl", "heterocyclic", or "heterocycloalkyl" refers to a heterocyclic group that is saturated or partially saturated, has 3 to 16, most preferably 5 to 10, and most preferably 1 or 4 ring atoms, and in which one or more, preferably 1 to 4, and especially 1 or 2 ring atoms are heteroatoms selected from oxygen, nitrogen, and sulfur (and therefore the remaining ring atoms are carbon). The term heterocyclyl excludes heteroaryl. Heterocyclic groups can be attached to the remainder of the molecule through a heteroatom selected from oxygen, nitrogen, and sulfur, or through a carbon atom. Heterocyclyl can include fused or bridged rings, and spirocyclic rings. Examples of heterocyclyls include dihydrofuranyl, dioxolanyl, dioxanyl, dithianyl, piperazinyl, pyrrolidine, dihydropyranyl, oxathiolanyl, dithiolane, oxathianyl, thiomorpholino, oxiranyl, aziridinyl, oxetanyl, oxepanyl, azetidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, morpholino, piperazinyl, azepinyl, oxapinyl, oxaazepanyl, oxathianyl, thiepanyl, azepanyl, dioxepanyl, and diazepanyl.

[0069] As used herein, the term "halogen" or "halo" refers to fluorine, chlorine, bromine and iodine.

[0070] As used herein, the term "aryl" refers to an aromatic ring system having any suitable number of ring atoms and any suitable number of rings. An aryl group can contain any suitable number of ring atoms, for example, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 ring atoms, and 6-10 ring members, 6-12 ring members, or 6-14 ring members. Aryl groups can be monocyclic, fused to form bicyclic or tricyclic groups, or linked by bonds to form biaryl groups. Representative aryl groups include phenyl, naphthyl, and biphenyl. Other aryl groups include benzyl with a methylene linking group. Some aryl groups have 6-12 ring members, for example, phenyl, naphthyl, or biphenyl. Other aryl groups have 6-10 ring members, for example, phenyl or naphthyl. Some other aryl groups have 6 ring members, for example, phenyl. Aryl groups can be substituted or unsubstituted.

[0071] The term "heteroaryl" refers to an aryl group (or ring) containing at least one heteroatom, such as N, O, or S, where the nitrogen and sulfur atoms are optionally oxidized and the nitrogen atom(s) are optionally quaternized. Additional heteroatoms may also be useful, including, but not limited to, B, Al, Si, and P. Heteroaryl groups can contain any number of ring atoms, such as 3-6 ring members, 4-6 ring members, 5-6 ring members, 3-8 ring members, 4-8 ring members, 5-8 ring members, 6-8 ring members, 3-9 ring members, 3-10 ring members, 3-11 ring members, or 3-12 ring members. Any suitable number of heteroatoms, such as 1, 2, 3, 4, or 5, or 1-2, 1-3, 1-4, 1-5, 2-3, 2-4, 2-5, 3-4, or 3-5, may be included in the heteroaryl group. Heteroaryl groups can have 5-9 ring members and 1-4 heteroatoms, or 5-9 ring members and 1-3 heteroatoms, or 5-6 ring members and 1-4 heteroatoms, or 5-6 ring members and 1-3 heteroatoms. Heteroaryl groups can include groups such as pyrrole, pyridine, imidazole, pyrazole, triazole, tetrazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4- and 1,3,5-isomers), purine, and the like. Heteroaryl groups can also be fused to aromatic ring systems, such as phenyl rings, to form members including, but not limited to, benzopyrroles, such as indole and isoindole, benzopyridines, such as quinoline and isoquinoline, benzopyrazine (quinoxaline), benzopyrimidine (quinazoline), benzopyridazines, such as phthalazine and cinnoline, benzothiophene, and benzofuran. Other heteroaryl groups include heteroaryl rings linked by bonds, such as bipyridine.Heteroaryl groups can be substituted or unsubstituted.

[0072] An "arylene" and a "heteroarylene," alone or as part of another substituent, mean a divalent radical derived from an aryl and heteroaryl, respectively. A heteroaryl group substituent can be attached to a ring heteroatom nitrogen through -O-.

[0073] symbol [ka] indicates the point of attachment of the chemical moiety to the remainder of the molecule or chemical formula.

[0074] The term "oxo" as used herein means an oxygen atom (=O) attached to an attachment point by a double bond. The term "thio" as used herein means a sulfur atom (=S) attached to an attachment point by a double bond.

[0075] Each of the above terms (e.g., "alkyl," "heteroalkyl," "cycloalkyl," "heterocycloalkyl," "aryl" and "heteroaryl") includes both substituted and unsubstituted forms of the specified radical. Preferred substituents for each type of radical are provided below.

[0076] "Substituent," as used herein, means a group selected from the following moieties: (A) Oxo, Thio, Halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -O CHI2, -OCHF2, -N3, unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (e.g., 2-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3-8 membered heterocycloalkyl, 3-6 membered heterocycloalkyl, or 5-6 membered heterocycloalkyl), unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5-10 membered heteroaryl, 5-9 membered heteroaryl, or 5-6 membered heteroaryl), and (B) alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), heteroalkyl (e.g., 2-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), heterocycloalkyl (e.g., 3-8 membered heterocycloalkyl, 3-6 membered heterocycloalkyl, or 5-6 membered heterocycloalkyl), aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl), heteroaryl (e.g., 5-10 membered heteroaryl, 5-9 membered heteroaryl, or 5-6 membered heteroaryl) [substituted with at least one substituent selected from the following: (i) Oxo, thio, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -O CHI2, -OCHF2, -N3, unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (e.g., 2-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3-8 membered heterocycloalkyl, 3-6 membered heterocycloalkyl, or 5-6 membered heterocycloalkyl), unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5-10 membered heteroaryl, 5-9 membered heteroaryl, or 5-6 membered heteroaryl), and (ii) alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), heteroalkyl (e.g., 2-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), heterocycloalkyl (e.g., 3-8 membered heterocycloalkyl, 3-6 membered heterocycloalkyl, or 5-6 membered heterocycloalkyl), aryl (e.g., C6-C 10 Aryl, C 10aryl, or phenyl), heteroaryl (e.g., 5-10 membered heteroaryl, 5-9 membered heteroaryl, or 5-6 membered heteroaryl) (substituted with at least one substituent selected from group (i)).

[0077] Certain compounds of the present disclosure have asymmetric carbon atoms (optical centers) or double bonds; the racemates, diastereomers, geometric isomers, positional isomers and individual isomers (e.g., separate enantiomers) are all intended to be encompassed within the scope of the present disclosure. In some embodiments, the compounds of the present disclosure are specific enantiomers, anomers, or diastereomers that are substantially free of other forms.

[0078] The terms "a," "an," and "the," as used herein, mean one or more and are intended to include the plural forms as well, unless the context clearly indicates otherwise.

[0079] For example, the phrase "substituted with" as used herein means that the specified group may be substituted with one or more of any or all of the named substituents. For example, a group such as an alkyl or heteroaryl group may be substituted with an "unsubstituted C1-C 20 When "substituted with alkyl, or unsubstituted 2-20 membered heteroalkyl," the group is selected from the group consisting of one or more unsubstituted C1-C 20 It may contain one or more unsubstituted 2-20 membered alkyls, and / or one or more unsubstituted 2-20 membered heteroalkyls.

[0080] The description of the compound of the present disclosure, or its pharma-ceutically acceptable salt, is limited by the principles of chemical bonding known to those skilled in the art.Therefore, when a group can be substituted by one or more of several substituents, such substitutions are selected to bring about a compound that is not inherently unstable according to the principles of chemical bonding and / or is known to those skilled in the art as likely to be unstable under ambient conditions, such as aqueous, neutral and some known physiological conditions.For example, heterocycloalkyl or heteroaryl is bonded to the rest of the molecule through ring heteroatom according to the principles of chemical bonding known to those skilled in the art, thereby avoiding inherently unstable compounds.

[0081] The term "solution" refers to a liquid mixture in which a minor component (eg, a solute or compound) is uniformly distributed within a major component (eg, a solvent).

[0082] The terms "bind," "bound," "affix," "affixed," "attach," or "attached," as used herein, are used according to their plain ordinary meaning and refer to an association between atoms or molecules. The association may be direct or indirect. For example, the bound atoms or molecules may be direct, e.g., by a covalent bond or linker (e.g., a first linker or a second linker), or indirect, e.g., by a non-covalent bond (e.g., electrostatic interactions (e.g., ionic bonds, hydrogen bonds, halogen bonds), van der Waals interactions (e.g., dipole-dipole, dipole-induced dipole, London dispersion forces), ring stacking (pi effect), hydrophobic interactions, etc.).

[0083] The term "pharmaceutical acceptable salts" is meant to include salts of active compounds prepared with relatively non-toxic acids or bases, depending on the specific substituents found on the compounds described herein. When the compounds of the present disclosure contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of salts derived from pharmaceutical acceptable inorganic bases include aluminum, ammonium, calcium, copper, iron (III), iron (II), lithium, magnesium, manganese (III), manganese (II), potassium, sodium, zinc, etc. Salts derived from pharma- ceutically acceptable organic bases include salts of primary, secondary, and tertiary amines, including substituted amines such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like, cyclic amines, naturally occurring amines, and the like. When a compound of the present disclosure contains a relatively basic functional group, an acid addition salt can be obtained by contacting the neutral form of such a compound, either neat or in a suitable inert solvent, with a sufficient amount of the desired acid.Examples of pharma- ceutically acceptable acid addition salts include those derived from inorganic acids such as hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydroiodic, or phosphorous acids, as well as salts derived from relatively non-toxic organic acids, such as acetic, propionic, isobutyric, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Also included are salts of amino acids, such as arginates, and organic acids, such as glucuronic or galactunoric acids (see, e.g., Berge, SM, et al, "Pharmaceutical Salts", Journal of Pharmaceutical Science, 1977, 66, 1-19).Certain compounds of the present disclosure contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.

[0084] The neutral forms of the compounds can be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but for purposes of this disclosure the salts are otherwise equivalent to the parent form of the compound.

[0085] The term "preparation" is intended to include the formulation of active compound with encapsulating material as a carrier to provide capsule, in which active ingredient is surrounded by a carrier with or without other carrier, thereby the active ingredient is associated with the carrier.Similarly, cachet and lozenge are included.Tablet, powder, capsule, pill, cachet and lozenge can be used as solid dosage form suitable for oral administration.

[0086] In this disclosure, "comprises," "comprising," "containing," "having," and the like can have the meaning ascribed to them in U.S. Patent Law and can mean "includes," "including," and the like. "Consisting essentially of" or "consists essentially of" likewise has the meaning ascribed to them in U.S. Patent Law and is open-ended, allowing for the presence of things other than what is recited, but excluding prior art embodiments, so long as the basic or novel characteristics recited are not altered by the presence of things other than what is recited.

[0087] All starting materials, building blocks, reagents, acids, bases, dehydrating agents, solvents, and catalysts utilized to synthesize the compounds of the present disclosure (e.g., Example 1) are either commercially available or can be produced by organic synthesis methods known to those of skill in the art.

[0088] In one aspect, the moiety: (i) a chelating ligand moiety (CL), (ii) an optical probe portion (OP); and (iii) Biological targeting moiety (BT) or a pharma- ceutically acceptable salt thereof.

[0089] In some embodiments, the compound further comprises a fluorine atom bearing moiety (FCM).

[0090] In some embodiments, the compound does not include a fluorine atom bearing moiety (FCM).

[0091] In one aspect, the moiety: (i) a fluorine atom-bearing moiety (FCM); (ii) a chelating ligand moiety (CL); (iii) an optical probe portion (OP); and (iv) Biological targeting moiety (BT) or a pharma- ceutically acceptable salt thereof.

[0092] In some embodiments, the compound further comprises a metal ion. In some embodiments, the metal ion is bound to a chelating ligand (CL). In some embodiments, the metal ion is selected from radioactive or non-radioactive isotopes of metals selected from Y, I, Lu, Sm, Re, Re, Cu, Pb, Ho, Sc, Ac, Bi, Bi, At, Pb, Th, and Ra. In some embodiments, the metal ion is 177 Lu, 225 In some embodiments, the metal ion is a cation of 125 I or 64 In some embodiments, 125 I or 64 Compounds containing a CL moiety bound to Cu are particularly useful for PET imaging. In some embodiments, the metal ion is 90 In some embodiments, 90 Compounds containing a CL moiety attached to Y are particularly useful for SPECT imaging.

[0093] In some embodiments, each of moieties (i)-(iv) of the compound of formula I is L 1 , L 2 , L 3 , L 4 , L 5 , L 6 and L 7 is linked to at least one other moiety by one or more linkers selected from:

[0094] L 1 is a bond, -L 1A , -L 1A -L 1B -, -L 1A -L 1B -L 1C -, -L 1AC(O)NR 11 IT 1B -,-IT 1A No. 11 IT 1B -,-IT 1A C(O)L 1B -,-IT 1A C(O)OL 1B -,-IT 1A OC(O)L 1B -,-IT 1A (OL 1B ) n1 -,-IT 1A No. 11 C(O)L 1B -,-IT 1A No. 11 C(O)OL 1B -、or-L 1A No. 11 (OL 1B ) n1 - it is.

[0095] IT 2 -L 2A ,-IT 2A -IT 2B -,-IT 2A- IT 2B -IT 2C -,-IT 2A C(O)NR 12 IT 2B -,-IT 2A No. 12 IT 2B -,-IT 2A C(O)L 2B -,-IT 2A C(O)OL 2B -,-IT 2A OC(O)L 2B -,-IT 2A (OL 2B ) n2 -,-IT 2A No. 12 C(O)L 2B -,-IT 2A No. 12 C(O)OL 2B -、or-L 2A No. 12 (OL 2B ) n2 - it is.

[0096] L 3 is a bond, -L 3A , -L 3A -L 3B - -L 3A -L 3B -L 3C -, -L 3A C(O)NR 13 L 3B -, -L 3A NR 13 L 3B -, -L 3A C(O)L 3B -, -L 3A C(O)OL 3B -, -L 3A OC(O)L 3B -, -L 3A (OL 3B ) n3 -, -L 3A NR 13 C(O)L 3B -, -L 3A NR 13 C(O)OL 3B -, or -L 3A NR 13 (OL 3B ) n3 -.

[0097] L 4 is a bond, -L 4A , -L 4A -L 4B -, -L 4A -L 4B -L 4C -, -L 4A C(O)NR 14 L 4B -, -L 4A NR 14 L 4B -, -L 4A C(O)L 4B -, -L 4A C(O)OL 4B -, -L 4A OC(O)L 4B -, -L 4A (OL 4B ) n4 -, -L 4A NR 14 C(O)L 4B -, -L4A NR 14 C(O)OL 4B - or -L 4A NR 14 (OL 4B ) n4 -It is.

[0098] L 5 teeth, [ka] It is.

[0099] L 6 teeth, [ka] It is.

[0100] L 7 teeth, [ka] It is.

[0101] Each L 1A , L 1B , L 1C , L 2A , L 2B , L 2C , L 3A , L 3B , L 3C , L 4A , L 4B , L 4C , L 5A , L 5B , L 6A , L 6B , L 7A , and L 7B is independently a bond, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene.

[0102] Each R 11 , R 12 , R13 , R 14 , R 15 , and R 16 is independently hydrogen and unsubstituted alkyl.

[0103] Each of n1, n2, n3, n4, n5, n6 and n7 is independently an integer from 0 to 20.

[0104] In some embodiments, each L 1A , L 1B , L 1C , L 2A , L 2B , L 2C , L 3A , L 3B , L 3C , L 4A , L 4B , and L 4C are independently a bond, unsubstituted C1 to C 12 Alkylene, unsubstituted 2-12 membered heteroalkylene, unsubstituted C3-C 12 It is cycloalkylene, unsubstituted 5- to 12-membered heterocycloalkylene, unsubstituted phenylene, or unsubstituted 5- to 12-membered heteroarylene.

[0105] In some embodiments, the FCM comprises one or more F 18 and F 19 In some embodiments, the FCM comprises one or more F 18 and F 19 In some embodiments, the FCM comprises, for example, -BF2- and / or -BF3. [ka] and one or more of F is F 18 / F 19 It is.

[0106] In some embodiments, the FCM comprises a -BF2- and / or -BF3 moiety, the -BF2- and / or -BF3 moiety being a group consisting of two or more F 18 In some embodiments, the -BF2- moiety comprises two F18 In some embodiments, the -BF3 moiety comprises two F 18 In some embodiments, the -BF3 moiety comprises three F 18 Includes.

[0107] In some embodiments, the FCM comprises a -BF2- and / or -BF3 moiety, the -BF2- and / or -BF3 moiety being a group consisting of two or more F 19 In some embodiments, the -BF2- moiety comprises two F 19 In some embodiments, the -BF3 moiety comprises two F 19 In some embodiments, the -BF3 moiety comprises three F 19 Includes.

[0108] In some embodiments, the OP comprises one or more fluorophores as described herein. In some embodiments, the OP comprises cyanine-based fluorophores and xanthene-based fluorophores. In some embodiments, the OP comprises one or more fluorescent or light-absorbing dyes and their derivatives. In some embodiments, the OP comprises Cy2, Cy3, Cy3B, Cy3.5, Cy5, Cy5.5, Cy7, or Cy9 (cyanine-based fluorophores). In some embodiments, the OP comprises rhodamine. In some embodiments, the OP comprises an azo dye, such as Evans Blue (the tetrasodium salt of 6,6'-{(3,3'-dimethyl[1,1'-biphenyl]-4,4'-diyl)bis[diazene-2,1-diyl]}bis(4-amino-5-hydroxynaphthalene-1,3-disulfonate) and isosulfan blue (lymphazurin).

[0109] In some embodiments, the BT comprises one or more selected from small molecules, prodrugs, cells, blood cells, peptides, oligosaccharides, nucleic acids, aptamers, targeting agents, antibodies, and antibody fragments. In some embodiments, the BT comprises one or more selected from, but not limited to, prostate specific membrane antigen (PSMA) targeting agents, fibroblast activation protein (FAP) inhibitors, fibronectin or integrin targeting agents, somatostatin targeting peptides, pentixafor chemokine receptors, antibodies, antibody fragments, reengineered antibody T cells, and heparin. Exemplary BTs are shown in FIG. 4, but examples are not limited thereto.

[0110] In some embodiments, BT does not contain a divalent or trivalent counter cation. In some embodiments, BT may contain a single reactive amine. In some embodiments, BT in the synthesis of a compound as described herein may contain one or more amines necessary for its biological function. In some embodiments, BT may contain an acid group (e.g., a carboxylic acid group) that is chemically protected. In some embodiments, BT may not contain unprotected secondary or primary amines or acids that would interfere with the reaction of a halomethylboronic acid pinacol ester with a tertiary amine in the synthesis of the compound, such as step e of FIG. 3C.

[0111] In some embodiments, the PSMA targeting agent is [ka] In some embodiments, the fibroblast activation protein (FAP) inhibitor comprises a moiety of: [ka] In some embodiments, the fibronectin or integrin targeting agent comprises a portion of [ka] In some embodiments, the pentixafor chemokine receptor comprises a portion of: [ka] In some embodiments, the somatostatin targeting peptide (e.g., SSTR2) comprises a portion of: [ka] Includes parts of.

[0112] In some embodiments, BT is [ka] or a pharma- ceutically acceptable salt thereof.

[0113] In some embodiments, the CL comprises one or more acyclic or macrocyclic derivatives containing ethylenediamine, aminoethylthiol, or a hexadentate ligand. In some embodiments, the CL comprises one or more of dodecanetetraacetic acid (DOTA), nitro-DOTA, 4-aminophenylethyl-1,4,7,10-tetraazacyclodecane-N,N',N'',N'''-tetraacetic acid (PA-DOTA), diethylenetriaminepentaacetic acid (DTPA), (2-[4,7-bis(carboxymethyl)-1,4,7-triazonan-1-yl]acetic acid) NOTA, (triethylenetetramine) TETA, desferrioxamine, (ethylenediaminetetraacetic acid) EDTA, and penicillamine, or a pharma- ceutically acceptable salt thereof.

[0114] In some embodiments, the compound has the structure of formula (I): [ka] FCM, CL, OP, BT, L 1 , L 2 , L 3 , L 4 and L 5 is as mentioned above.

[0115] In some embodiments, L 5 teeth, [ka] It is.

[0116] In some embodiments, the compound has the structure of formula (Ia): [ka] FCM, CL, OP, BT, L 1 , L 2 , L 3 , and L 4 has been mentioned above.

[0117] In some embodiments, in formula (I) or (Ia), L 1 -L 1A -L 1B -L 1C In some embodiments, L 1A is unsubstituted C1-C 12 alkylene, or oxo- or thio-substituted or unsubstituted 2-12 membered heteroalkylene. In some embodiments, L 1B is unsubstituted phenylene. In some embodiments, L 1C is unsubstituted C1-C 12 It is alkylene, or oxo- or thio-substituted or unsubstituted 2- to 12-membered heteroalkylene.

[0118] In some embodiments, L 1A is unsubstituted C1-C 12 alkylene, L 1B is unsubstituted phenylene; L 1C is an oxo- or thio-substituted or unsubstituted 2-12 membered heteroalkylene. 1A is methylene. In some embodiments, L 1A is an oxo- or thio-substituted or unsubstituted 2- to 12-membered heteroalkylene; L 1Bis unsubstituted phenylene; L 1C is unsubstituted C1-C 12 In some embodiments, L is alkylene. 2C is methylene. In some embodiments, L 1 teeth, [ka] It is.

[0119] In some embodiments, L 1 -L 1A C(O)NR 11 L 1B - or -L 1A NR 11 C(O)L 1B In some embodiments, L 1A and L 1B are independently unsubstituted C1 to C 12 In some embodiments, L is an alkylene or an unsubstituted phenylene. 1A is unsubstituted C1-C 12 alkylene, L 1B is unsubstituted phenylene. In some embodiments, L 1A is unsubstituted phenylene; L 1B is unsubstituted C1-C 12 In some embodiments, R is an alkylene. 11 is hydrogen. In some embodiments, L 1 teeth, [ka] It is.

[0120] In some embodiments, L 2 is unsubstituted C1-C 12 In some embodiments, L is alkylene. 3 is unsubstituted C1-C 12 In some embodiments, each L 2 and L 3 are independently unsubstituted C1 to C 12 It is alkylene.

[0121] In some embodiments, L 4 is unsubstituted C1-C 12 Alkylene or -L 4A NC(O)L 4B In some embodiments, L 4A and L 4B are independently a bond or an unsubstituted C1-C 12 In some embodiments, L is alkylene. 4A is a bond, and L 4B is unsubstituted C1-C 12 In some embodiments, L is alkylene. 4A is unsubstituted C1-C 12 alkylene, L 4B is a bond.

[0122] In some embodiments, the compound has the structure of formula (Ia-1): [ka] FCM, OP, BT, L 1A , L 1C , L 2 , L 3 , and L 4 has been mentioned above.

[0123] In some embodiments, L 1A is an oxo-substituted or unsubstituted 2-12 membered heteroalkylene. 1C is unsubstituted C1-C 12 It is alkylene.

[0124] In some embodiments, L 1A teeth, [ka] It is.

[0125] In some embodiments, L 1C is unsubstituted methylene. In some embodiments, L1C is unsubstituted ethylene.

[0126] In some embodiments, the compound is [ka] [ka] [ka] [ka] [ka] or a pharma- ceutically acceptable salt thereof.

[0127] In some embodiments, the compound has the structure of formula (II) [ka] FCM, CL, OP, BT, L 1 , L 2 , L 3 , L 4 and L 5 has been mentioned above.

[0128] In some embodiments, L 1 is a bond or unsubstituted C1-C 12 In some embodiments, L is alkylene. 1 is a bond. In some embodiments, L 1 is methylene.

[0129] In some embodiments, L 5 teeth, [ka] It is.

[0130] In some embodiments, L2 -L 2A -L 2B -L 2C In some embodiments, each L 2A , L 2B , and L 2C are independently a bond, unsubstituted C1 to C 12 In some embodiments, L is an alkylene or an oxo- or thio-substituted 5-10 membered heteroalkyl. 2A is a bond, unsubstituted C1-C 12 In some embodiments, L is an alkylene or an oxo- or thio-substituted 5-10 membered heteroalkyl. 2B is a bond, unsubstituted C1-C 12 In some embodiments, L is an alkylene or an oxo- or thio-substituted 5-10 membered heteroalkyl. 2C is a bond, unsubstituted C1-C 12 It is alkylene, or an oxo- or thio-substituted 5-10 membered heteroalkyl.

[0131] In some embodiments, L 3 -L 3A -L 3B -L 3C In some embodiments, L 3A is unsubstituted C1-C 12 alkylene, or oxo- or thio-substituted or unsubstituted 2-12 membered heteroalkylene. In some embodiments, L 3B is unsubstituted phenylene. In some embodiments, L 3C is unsubstituted C1-C 12 It is alkylene, or oxo- or thio-substituted or unsubstituted 2- to 12-membered heteroalkylene.

[0132] In some embodiments, L 3A is unsubstituted C1-C 12 alkylene, L 3B is unsubstituted phenylene; L 3C is an oxo- or thio-substituted or unsubstituted 2-12 membered heteroalkylene. 3Ais methylene. In some embodiments, L 3A is an oxo- or thio-substituted or unsubstituted 2- to 12-membered heteroalkylene; L 3B is unsubstituted phenylene; L 3C is unsubstituted C1-C 12 In some embodiments, L is alkylene. 3C is methylene.

[0133] In some embodiments, L 4 -L 4A -L 4B -L 4C In some embodiments, L 4A is unsubstituted C1-C 12 alkylene, or oxo- or thio-substituted or unsubstituted 2-12 membered heteroalkylene. In some embodiments, L 4B is unsubstituted phenylene. In some embodiments, L 4C is unsubstituted C1-C 12 It is alkylene, or oxo- or thio-substituted or unsubstituted 2- to 12-membered heteroalkylene.

[0134] In some embodiments, L 4A is unsubstituted C1-C 12 alkylene, L 4B is unsubstituted phenylene; L 4C is an oxo- or thio-substituted or unsubstituted 2-12 membered heteroalkylene. 4A is methylene. In some embodiments, L 4A is an oxo- or thio-substituted or unsubstituted 2- to 12-membered heteroalkylene; L 4B is unsubstituted phenylene; L 4C is unsubstituted C1-C 12 In some embodiments, L is alkylene. 4C is methylene.

[0135] In some embodiments, the compound is [ka] or a pharma- ceutically acceptable salt thereof.

[0136] In some embodiments, the compound is [ka] FCM, CL, OP, BT, L 1 , L 2 , L 5 and L 6 has been mentioned above.

[0137] In some embodiments, in formula (III), L 1 -L 1A -L 1B -L 1C In some embodiments, L 1A is unsubstituted C1-C 12 alkylene, or oxo- or thio-substituted or unsubstituted 2-12 membered heteroalkylene. In some embodiments, L 1B is unsubstituted phenylene. In some embodiments, L 1C is unsubstituted C1-C 12 It is alkylene, or oxo- or thio-substituted or unsubstituted 2- to 12-membered heteroalkylene.

[0138] In some embodiments, L 1A is unsubstituted C1-C 12 alkylene, L 1B is unsubstituted phenylene; L 1C is an oxo- or thio-substituted or unsubstituted 2-12 membered heteroalkylene. 1A is methylene. In some embodiments, L 1A is an oxo- or thio-substituted or unsubstituted 2- to 12-membered heteroalkylene; L 1B is unsubstituted phenylene; L 1C is unsubstituted C1-C 12 In some embodiments, L is alkylene.1C is methylene. In some embodiments, L 1 teeth, [ka] It is.

[0139] In some embodiments, L 1 -L 1A C(O)NR 11 L 1B - or -L 1A NR 11 C(O)L 1B In some embodiments, L 1A and L 1B are independently unsubstituted C1 to C 12 In some embodiments, L is an alkylene or an unsubstituted phenylene. 1A is unsubstituted C1-C 12 alkylene, L 1B is unsubstituted phenylene. In some embodiments, L 1A is unsubstituted phenylene; L 1B is unsubstituted C1-C 12 In some embodiments, R is an alkylene. 11 is hydrogen. In some embodiments, L 1 teeth, [ka] It is.

[0140] In some embodiments, L 2 is unsubstituted C1-C 12 It is alkylene.

[0141] In some embodiments, L 5 teeth, [ka] In some embodiments, L 5A and L 5B are independently a bond, unsubstituted C1 to C 12In some embodiments, L is an alkylene or an oxo- or thio-substituted 5-10 membered heteroalkyl. 5A is a bond, unsubstituted C1-C 12 In some embodiments, L is an alkylene or an oxo- or thio-substituted 5-10 membered heteroalkyl. 5B is a bond, unsubstituted C1-C 12 It is alkylene, or an oxo- or thio-substituted 5-10 membered heteroalkyl.

[0142] In some embodiments, L 5 teeth, [ka] In some embodiments, L 6 teeth, [ka] In some embodiments, L 5 -L 6 teeth, [ka] It is.

[0143] In some embodiments, the compound is [ka] or a pharma- ceutically acceptable salt thereof.

[0144] In some embodiments, the compound is [ka] FCM, CL, OP, BT, L 2 , L 3 , L 4 and L 5 has been mentioned above.

[0145] In some embodiments, in formula (IV-a) or (IV-b), L 2 -L 2A -L 2B -L 2C In some embodiments, L 2A is unsubstituted C1-C 12 alkylene, or oxo- or thio-substituted or unsubstituted 2-12 membered heteroalkylene. In some embodiments, L 2B is unsubstituted phenylene. In some embodiments, L 2C is unsubstituted C1-C 12 It is alkylene, or oxo- or thio-substituted or unsubstituted 2- to 12-membered heteroalkylene.

[0146] In some embodiments, L 2A is unsubstituted C1-C 12 alkylene, L 2B is unsubstituted phenylene; L 2C is an oxo- or thio-substituted or unsubstituted 2-12 membered heteroalkylene. 2A is methylene. In some embodiments, L 2A is an oxo- or thio-substituted or unsubstituted 2- to 12-membered heteroalkylene; L 2B is unsubstituted phenylene; L 2C is unsubstituted C1-C 12 In some embodiments, L is alkylene. 2C is methylene. In some embodiments, L 2 teeth, [ka] It is.

[0147] In some embodiments, in formula (IV-a) or (IV-b), L 3 -L 3A -L 3B -L 3C In some embodiments, L 3A is unsubstituted C1-C 12alkylene, or oxo- or thio-substituted or unsubstituted 2-12 membered heteroalkylene. In some embodiments, L 3B is unsubstituted phenylene. In some embodiments, L 3C is unsubstituted C1-C 12 It is alkylene, or oxo- or thio-substituted or unsubstituted 2- to 12-membered heteroalkylene.

[0148] In some embodiments, L 3A is unsubstituted C1-C 12 alkylene, L 3B is unsubstituted phenylene; L 3C is an oxo- or thio-substituted or unsubstituted 2-12 membered heteroalkylene. 3A is methylene. In some embodiments, L 3A is an oxo- or thio-substituted or unsubstituted 2- to 12-membered heteroalkylene; L 3B is unsubstituted phenylene; L 3C is unsubstituted C1-C 12 In some embodiments, L is alkylene. 3C is methylene. In some embodiments, L 3 teeth, [ka] It is.

[0149] In some embodiments, L 3 -L 3A C(O)NR 13 L 3B - or -L 3A NR 13 C(O)L 3B In some embodiments, L 3A and L 3B are independently unsubstituted C1 to C 12 In some embodiments, L is an alkylene or an unsubstituted phenylene. 3A is unsubstituted C1-C 12 alkylene, L 3Bis unsubstituted phenylene. In some embodiments, L 3A is unsubstituted phenylene; L 3B is unsubstituted C1-C 12 In some embodiments, R is an alkylene. 11 is hydrogen. In some embodiments, L 3 teeth, [ka] It is.

[0150] In some embodiments, L 4 -L 4A -L 4B , -L 4A C(O)NR 14 L 4B - or -L 4A NR 14 C(O)L 4B In some embodiments, each L 4A and L 4B are independently unsubstituted C1 to C 12 alkylene, or oxo- or thio-substituted or unsubstituted 2-12 membered heteroalkylene. In some embodiments, L 4A is unsubstituted C1-C 12 alkylene, or oxo- or thio-substituted or unsubstituted 2-12 membered heteroalkylene. In some embodiments, L 4B is unsubstituted C1-C 12 It is alkylene, or oxo- or thio-substituted or unsubstituted 2- to 12-membered heteroalkylene.

[0151] In some embodiments, the compound is [ka] or a pharma- ceutically acceptable salt thereof.

[0152] In some embodiments, the compound is [ka] FCM, CL, OP, BT, L 1 , L 2 , L 3 , and L 4 has been mentioned above.

[0153] In some embodiments, the compound is [ka] FCM, CL, OP, BT, L 1 , L 2 , L 4 , and L 5 has been mentioned above.

[0154]

[0155] In some embodiments, in formula (V), L 7 teeth, [ka] In some embodiments, each L 7A and L 7B are independently a bond, unsubstituted C1 to C 12 In some embodiments, L is an alkylene, an oxo- or thio-substituted or unsubstituted 2- to 12-membered heteroalkylene, or an unsubstituted phenylene. 7A is a bond, unsubstituted C1-C 12 In some embodiments, L is an alkylene, an oxo- or thio-substituted or unsubstituted 2- to 12-membered heteroalkylene, or an unsubstituted phenylene. 7B is a bond, unsubstituted C1-C 12 In some embodiments, L is an alkylene, an oxo- or thio-substituted or unsubstituted 2- to 12-membered heteroalkylene, or an unsubstituted phenylene. 7 teeth, [ka] It is.

[0156] In some embodiments, L 1 -L 1A -L 1B -L 1C In some embodiments, L 1A is unsubstituted C1-C 12 alkylene, or oxo- or thio-substituted or unsubstituted 2-12 membered heteroalkylene. In some embodiments, L 1B is unsubstituted phenylene. In some embodiments, L 1C is unsubstituted C1-C 12 It is alkylene, or oxo- or thio-substituted or unsubstituted 2- to 12-membered heteroalkylene.

[0157] In some embodiments, L 1A is unsubstituted C1-C 12 alkylene, L 1B is unsubstituted phenylene; L 1C is an oxo- or thio-substituted or unsubstituted 2-12 membered heteroalkylene. 1A is methylene. In some embodiments, L 1A is an oxo- or thio-substituted or unsubstituted 2- to 12-membered heteroalkylene; L 1B is unsubstituted phenylene; L 1C is unsubstituted C1-C 12 In some embodiments, L is alkylene. 1C is methylene. In some embodiments, L 1 teeth, [ka] It is.

[0158] In some embodiments, L 2 -L 2A -L 2B -L 2C In some embodiments, L 3 -L 3A -L 3B -L 3C In some embodiments, L4 -L 4A -L 4B -L 4C In some embodiments, each L 2A , L 2B , L 2C , L 3A , L 3B , L 3C , L 4A , L 4B , and L 4C are independently a bond, unsubstituted C1 to C 12 It is alkylene, or oxo- or thio-substituted or unsubstituted 2- to 12-membered heteroalkylene.

[0159] In some embodiments, the compound is [ka] [ka] [ka] or a pharma- ceutically acceptable salt thereof.

[0160] In some embodiments, the compound is [ka] or a pharma- ceutically acceptable salt thereof.

[0161] In some embodiments, exemplary compounds are summarized in Table 1 below. [Table 1-1] [Table 1-2]

[0162] In one aspect, the moiety: (i) a chelating ligand moiety (CL), (ii) an optical probe portion (OP); and (iii) Biological targeting moiety (BT) wherein the compound has a structure of formula (X):

[0163] In some embodiments, the compound has the structure of formula (X): [ka] CL, OP, BT, L 1 , L 3 , L 4 and L 5 has been mentioned above.

[0164] In some embodiments, the compound has the structure of formula (Xa): [ka] CL, OP, BT, L 1 , L 3 , and L 4 has been mentioned above.

[0165] In some embodiments, the compound has the structure of formula (XI): [ka] CL, OP, BT, L 1 , L 3 , L 4 , and L 5 has been mentioned above.

[0166] In some embodiments, the compound has the structure of formula (XII): [ka] CL, OP, BT, L 1 , L 5 , and L 6 has been mentioned above.

[0167] In some embodiments, the compound has the structure of formula (XIII-a) or (XIII-b) [ka] CL, OP, BT, L 3 , and L 4 has been mentioned above.

[0168] In some embodiments, the compound is [ka] or a pharma- ceutically acceptable salt thereof.

[0169] In some embodiments, the compound has the structure of formula (XIV-a) or (XIV-b) [ka] CL, OP, BT, L 1 , L 3 , L 4 , and L 7 has been mentioned above.

[0170] In another aspect, a precursor of the compounds described herein is provided. In some embodiments, the precursor comprises a protecting group (e.g., tert-butyloxycarbonyl (BOC), 9-fluorenylmethyloxycarbonyl (Fmoc), acetyl (Ac), β-methoxyethoxymethylether (MEM), dimethoxytrityl, [bis-(4-methoxyphenyl)phenylmethyl] (DMT), carbobenzyloxy (Cbz), or p-methoxybenzylcarbonyl (Moz or MeOZ)). In some embodiments, the precursor is deprotected to generate the compounds described herein.

[0171] In some embodiments, the precursor has the structure [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] or a pharma- ceutically acceptable salt thereof.

[0172] In some embodiments, the precursor is [ka] or a pharma- ceutically acceptable salt thereof.

[0173] In some embodiments, the precursor is [ka] or a pharma- ceutically acceptable salt thereof. In some embodiments, the precursor is [ka] or a pharma- ceutically acceptable salt thereof.

[0174] In some embodiments, the compounds described herein or precursors thereof further comprise a metal atom or a metal ion thereof. In some embodiments, the compounds as described herein or precursors thereof are combined with a metal atom or an ion thereof such that the metal atom / ion can bind to the chelating ligand portion (CL) of the compound. Pharmaceutical Compositions

[0175] In another aspect, there is provided a pharmaceutical composition ("Composition") comprising a compound of Formula (I), (Ia), (Ia-1), (II), (III), (IV-a), (IV-b), (Va), (Vb), (VI-a), (VI-b), (X), (Xa), (XI), (XII), (XIII-a), (XIII-b), (XIV-a) or (XIV-b), or any subembodiment described herein, and one or more excipients or carriers, preferably pharma- ceutically acceptable excipients or carriers.

[0176] As used herein, the phrase "pharmaceutical acceptable" refers to compounds, materials, compositions, carriers, and / or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissues without undue toxicity, irritation, allergic response, or other problems or complications, and that meet a reasonable benefit / risk ratio. Excipients for preparing pharmaceutical compositions are generally excipients known to be safe and non-toxic when administered to the human or animal body. Examples of pharmaceutical acceptable excipients include, but are not limited to, sterile liquids, water, buffered saline, ethanol, polyols (e.g., glycerol, propylene glycol, liquid polyethylene glycol, etc.), oils, detergents, suspending agents, carbohydrates (e.g., glucose, lactose, sucrose, or dextran), antioxidants (e.g., ascorbic acid or glutathione), chelating agents, low molecular weight proteins, and suitable mixtures of any of the above. The particular excipients utilized in the composition will depend on a variety of factors, including the chemical stability and solubility of the compound being formulated, as well as the intended route of administration.

[0177] Pharmaceutical compositions can be provided in bulk or in unit dosage form.It is particularly advantageous to formulate pharmaceutical compositions into unit dosage form for ease of administration and uniformity of dosage.The term "unit dosage form" refers to a physically separate unit suitable as a unit dosage for the subject to be treated, each unit containing a predetermined amount of active compound calculated to produce the desired therapeutic effect together with necessary pharmaceutical carriers.Unit dosage form can be ampoules, vials, suppositories, dragees, tablets, capsules, IV bags, or a single pump pump in aerosol inhalers.

[0178] In therapeutic applications, dosage may vary according to the chemical and physical properties of active compounds and the clinical characteristics of subjects, including, for example, age, weight and comorbidities.Generally, dosage should be a therapeutically effective amount.The effective amount of pharmaceutical composition is the amount that produces an objectively identifiable improvement that is recognized by clinicians or other qualified observers.For example, the alleviation of symptoms of disorders, diseases or conditions.

[0179] The pharmaceutical composition may take any form (e.g., liquid, aerosol, solution, inhalant, mist, spray, or solid, powder, ointment, paste, cream, lotion, gel, patch, etc.) suitable for administration by any desired route (e.g., pulmonary, inhalation, intranasal, oral, buccal, sublingual, parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, intrapleural, intrathecal, transdermal, transmucosal, rectal, etc.). In some embodiments, the pharmaceutical composition is in the form of an orally acceptable dosage form, including, but not limited to, capsules, tablets, buccal forms, lozenges, lozenges, and oral liquids in the form of emulsions, aqueous suspensions, dispersions, or solutions. Capsules may contain excipients such as inert fillers and / or diluents, including starch (e.g., corn, potato, or tapioca starch), sugar, artificial sweeteners, powdered cellulose, such as crystalline and microcrystalline cellulose, flour, gelatin, gums, and the like. In the case of tablets for oral use, carriers which are commonly used include lactose and corn starch, Lubricating agents, such as magnesium stearate, can also be added.

[0180] In some embodiments, the pharmaceutical composition is in the form of a tablet. The tablet can contain a unit dose of the compound described herein together with an inert diluent or carrier, such as a sugar or sugar alcohol, such as lactose, sucrose, sorbitol or mannitol. The tablet can further contain a non-sugar derived diluent, such as sodium carbonate, calcium phosphate, calcium carbonate, or cellulose or its derivatives, such as methylcellulose, ethylcellulose, hydroxypropylmethylcellulose, and starch, such as corn starch. The tablet can further contain a binder and granulating agent, such as polyvinylpyrrolidone, a disintegrant (e.g., a swellable cross-linked polymer, such as cross-linked carboxymethylcellulose), a lubricant (e.g., stearate), a preservative (e.g., parabens), an antioxidant (e.g., butylated hydroxytoluene), a buffering agent (e.g., phosphate or citrate buffer), and an effervescent agent, such as a citrate / bicarbonate mixture. The tablet can be a coated tablet. The coating may be a protective film coating (e.g., a wax or varnish) or a coating designed to control the release of the active compound, for example to provide delayed release (releasing the active substance after a predefined delay time after ingestion) or to release at a particular location in the gastrointestinal tract. The latter can be achieved, for example, using enteric film coatings, such as those sold under the trade name Eudragit®.

[0181] Tablet formulations can be prepared by conventional compression, wet granulation or dry granulation methods, utilizing pharma- ceutically acceptable diluents, binders, lubricants, disintegrants, surface modifiers (including surfactants), suspending agents or stabilizers, including, but not limited to, magnesium stearate, stearic acid, talc, sodium lauryl sulfate, microcrystalline cellulose, calcium carboxymethylcellulose, polyvinylpyrrolidone, gelatin, alginic acid, gum acacia, xanthan gum, sodium citrate, complex silicates, calcium carbonate, glycine, dextrin, sucrose, sorbitol, dicalcium phosphate, calcium sulfate, lactose, kaolin, mannitol, sodium chloride, talc, dry starch and powdered sugar. Preferred surface modifiers include nonionic and anionic surface modifiers. Representative examples of surface modifiers include, but are not limited to, poloxamer 188, benzalkonium chloride, calcium stearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, colloidal silicon dioxide, phosphates, sodium dodecyl sulfate, magnesium aluminum silicate, and triethanolamine.

[0182] In some embodiments, the pharmaceutical composition is in the form of a hard or soft gelatin capsule. According to this formulation, the compounds of the present disclosure may be in solid, semi-solid, or liquid form.

[0183] In some embodiments, the pharmaceutical compositions are in the form of a sterile aqueous solution or dispersion suitable for parenteral administration, the term parenteral as used herein including subcutaneous, intradermal, intravenous, intramuscular, intra-articular, intra-arterial, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.

[0184] In some embodiments, the pharmaceutical composition is in the form of a sterile aqueous solution or dispersion suitable for administration by direct injection or by addition to a sterile infusion fluid for intravenous infusion, and includes a solvent or dispersion medium containing water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), a suitable mixture thereof, or one or more vegetable oils. The solution or suspension can be prepared in water with a co-solvent or surfactant. Examples of suitable surfactants include polyethylene glycol (PEG)-fatty acids and PEG-fatty acid mono- and diesters, PEG glycerol esters, alcohol-oil transesterification products, polyglyceryl fatty acids, propylene glycol fatty acid esters, sterols and sterol derivatives, polyethylene glycol sorbitan fatty acid esters, polyethylene glycol alkyl ethers, sugars and their derivatives, polyethylene glycol alkyl phenols, polyoxyethylene-polyoxypropylene (POE-POP) block copolymers, sorbitan fatty acid esters, ionic surfactants, fat-soluble vitamins and their salts, water-soluble vitamins and their amphiphilic derivatives, amino acids and their salts, and organic acids and their esters and anhydrides. Dispersions can also be prepared in, for example, glycerol, liquid polyethylene glycols and mixtures thereof in oils. How to use

[0185] In one aspect, there is provided a method of imaging biological tissue in a subject, the method comprising administering to the subject a compound of Formula (I), (Ia), (Ia-1), (II), (III), (IV-a), (IV-b), (Va), (Vb), (VI-a), (VI-b), (X), (Xa), (XI), (XII), (XIII-a), (XIII-b), (XIV-a) or (XIV-b), or a pharma- ceutically acceptable salt thereof, or any subembodiment described herein, or a pharmaceutical composition comprising same. In some embodiments, the method further comprises performing one or more imaging techniques selected from computed tomography (CT), positron emission tomography (PET), single photon emission computed tomography (SPECT), magnetic resonance imaging (MRI), contrast-assisted (e.g., gadolinium contrast) magnetic resonance imaging (cMRI), magnetic resonance angiography (MRA), and optical or fluorescence-based imaging (FL), and any combination of the above. In some embodiments, the method comprises simultaneously performing at least two imaging techniques selected from two of the above. In some embodiments, the at least two imaging techniques are selected from an optical fluorescence-based imaging (FL) technique, and an imaging technique selected from CT, PET, SPECT, MRI, cMRI and MRA, or a combination thereof.

[0186] In one aspect, a method of treating cancer in a subject using radioisotope therapy is provided, comprising administering to a subject a compound of Formula (I), (Ia), (Ia-1), (II), (III), (IV-a), (IV-b), (Va), (Vb), (VI-a), (VI-b), (X), (Xa), (XI), (XII), (XIII-a), (XIII-b), (XIV-a) or (XIV-b), or a pharma- ceutically acceptable salt thereof, or any subembodiment described herein, or a pharmaceutical composition comprising same, wherein the compound comprises a radioisotope suitable for radioisotope therapy, e.g., a radionuclide complexed to the CL moiety of the compound, or a radionuclide that forms part of the BT moiety, e.g., a radiolabeled antibody suitable for radioimmunotherapy. Radionuclides, particularly beta (β)- and alpha (α)-emitters, as well as radiohalogens and radiometals suitable for incorporation into the compounds described herein are set forth in Table 2. [Table 2]

[0187] For example, radioactive halogens 125 I, 123 I, 131 I, 211 At, 77 Br, and 80 Br can be introduced via the BT moiety, e.g., PSMA targeting agents. These radioactive halogens can be covalently bound to the targeting moiety, and unlike large chelated radioactive metals, are small enough that the entirety of the radiolabeled PSMA inhibitor can fit into the PSMA binding cavity, thereby retaining high binding affinity. In another example, the same radiolabeled prosthetic group can be attached to the urea bond of the linker-inhibitor to move the radiolabeled portion of the inhibitor to the outside of the protein.

[0188] In one aspect, a method is provided for treating a disease (e.g., cancer) or condition in a subject by administering any of the aforementioned compounds or compositions to the subject, wherein the compound comprises a therapeutic moiety, such as an RIT agent or an agent suitable for radioimmunotherapy, so that imaging and treatment are achieved using the same molecule. According to such a method, imaging of biological tissue can be performed before, in situ, and after treatment (e.g., surgical treatment) or treatment (e.g., radiation therapy), or any combination thereof.

[0189] In some embodiments, the present disclosure provides a method for image-guided surgery using the compounds described herein.In some embodiments, the surgery is tumor resection surgery, and the BT moiety is a biomarker that allows the compound to target the cancer tissue to be resected by the surgeon.

[0190] As used herein, the term "cancer" refers to any type of cancer, neoplasm, solid tumor, or malignant tumor found in a mammal (e.g., human), including leukemia, lymphoma, carcinoma, and sarcoma.Exemplary cancers that can be treated with the compounds or methods provided herein include brain cancer, glioma, glioblastoma, neuroblastoma, prostate cancer, colorectal cancer, pancreatic cancer, medulloblastoma, melanoma, cervical cancer, gastric cancer, ovarian cancer, lung cancer, head cancer, Hodgkin's disease, and non-Hodgkin's lymphoma.Exemplary cancers that can be treated with the compounds or methods provided herein include thyroid, endocrine system, brain, breast, cervix, colon, head and neck, liver, kidney, lung, ovary, pancreas, rectum, stomach, and uterine cancer. Further examples include thyroid cancer, bile duct cancer, pancreatic adenocarcinoma, cutaneous melanoma, colon adenocarcinoma, rectal adenocarcinoma, gastric adenocarcinoma, esophageal cancer, squamous cell carcinoma of the head and neck, invasive breast cancer, lung adenocarcinoma, squamous cell carcinoma of the lung, non-small cell lung cancer, mesothelioma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, ovarian cancer, rhabdomyosarcoma, primary thrombocytosis, primary macroglobulinemia, primary brain tumors, malignant pancreatic insulanoma, malignant carcinoid, bladder cancer, premalignant skin lesions, testicular cancer, thyroid cancer, neuroblastoma, esophageal cancer, genitourinary cancer, malignant hypercalcemia, endometrial cancer, adrenal cortical carcinoma, intrapancreatic or exocrine pancreatic neoplasms, medullary thyroid cancer, medullary thyroid carcinoma, melanoma, colorectal cancer, papillary thyroid carcinoma, hepatocellular carcinoma, or prostate cancer.

[0191] As used herein, the term "administering" refers to any means for delivering an agent to the subject's body via any known method. In some embodiments, administration methods include, but are not limited to, intravenous, oral, intramuscular, subcutaneous, and intratumoral administration. In some embodiments, administration is intravenous or intratumoral.

[0192] In one aspect, a method of imaging biological tissue using two or more imaging techniques selected from (i) positron emission tomography (PET) or single photon emission computed tomography (SPECT), (ii) computed tomography (CT), magnetic resonance imaging (MRI), and / or magnetic resonance angiography (MRA), and (iii) optical fluorescence-based imaging, comprising: (VI-b), (X), (Xa), (XI), (XII), (XIII-a), (XIII-b), (XIV-a) or (XIV-b), or a pharma- ceutically acceptable salt thereof, or any subembodiment described herein, or a pharmaceutical composition comprising same, to a subject, wherein the compound comprises each of (1) an FCM or CL, (2) an OP, and (3) a BT, or optionally wherein the compound comprises each of (1) an FCM, (2) a CL, (3) an OP, and (4) a BT.

[0193] According to any of the embodiments described herein that include imaging, the signal or scanned image can be obtained in situ or ex-situ during the process of treating or diagnosing a subject according to the method known in the art, for example, the method for performing PET, CT, MRI, cMRI, and SPECT imaging.For example, the method for imaging biological tissue using PET or SPECT is described in P. Zanzonico, Seminars in Nuclear Medicine, vol. XXXIV, No. 2, pp. 87-111, April 2004; G. Mariani et al., Eur. J. Vucl. Med. Mol. Imaging, DOI 10.1007 / s00259-010-1390-8, February 2010, and A. Rahmim et al., Nucl. Med. Commun., 29:193-207, 2008, the contents of which are incorporated herein by reference in their entirety.

[0194] In embodiments of the methods described herein, the combination of two or more imaging methods advantageously allows for overlay of different types of data for improved imaging and treatment. For example, data obtained from high-resolution images (e.g., from MRI and / or CT) and / or three-dimensional images (e.g., from PET, MRI, cMRI and / or SPECT) can be overlaid with optical fluorescence-based images. Optical fluorescence-based images can be obtained using OP moieties that include any dye moiety that allows for fluorescence detection (e.g., in the range of 400-1000 nm, including the visible and near-infrared (NIR) spectra). In specific examples, the methods can include (1) an initial imaging step in which a radioactive signal is detected from the FCM moiety, for example, using PET imaging, to determine the exact location of the tissue or organ of interest, and (2) a second imaging step in which a fluorescent signal emitted from the OP moiety is detected, which can be used to guide the surgeon during the surgical procedure. Thus, in some embodiments, the compounds described herein include at least two different detectable signals: (i) radioactivity from the FCM moiety and / or CL moiety, and (ii) fluorescence from the OP moiety. As used herein, the term "detectable" refers to detectable using two or more of the imaging methods described herein.

[0195] In some embodiments, a method of imaging biological tissue comprises: (i) administering to a subject a compound of Formula (I), (Ia), (Ia-1), (II), (III), (IV-a), (IV-b), (Va), (Vb), (X), (Xa), (XI), (XII), (XIII-a), (XIII-b), (XIV-a) or (XIV-b), or a pharma- ceutically acceptable salt thereof, or any subembodiment described herein, or a pharmaceutical composition comprising same; and (ii) administering to a subject a compound of Formula (I), (Ia), (Ia-1), (II), (III), (IV-a), (IV-b), (Va), (Vb), (X), (Xa), (XI), (XII), (XIII-a), (XIII-b), (XIV-a) or (XIV-b), or a pharma- ceutically acceptable salt thereof, or any subembodiment described herein, or a pharmaceutical composition comprising same; (iii) performing an imaging technique selected from CT, (iii) performing an imaging technique selected from CT, MRI, cMRI, and MRA, and optionally (iv) performing an imaging technique selected from optical or fluorescence-based imaging (FL) techniques, wherein the compound comprises three or more of (1) FCM, (2) CL, (3) OP, and (4) BT, and the compound emits a detectable signal suitable for performing each of the imaging techniques. In some embodiments, the imaging techniques are performed simultaneously or sequentially, or a combination thereof.

[0196] In some embodiments, methods are provided for treating a patient suffering from internal bleeding caused either by a tumor or other trauma, wherein the BT moiety is a red blood cell or a platelet, and the compound localizes to the site of bleeding.

[0197] In some embodiments, the BT moiety of a compound of formula (I), (Ia), (Ia-1), (II), (III), (IV-a), (IV-b), (Va), (Vb), (X), (Xa), (XI), (XII), (XIII-a), (XIII-b), (XIV-a), or (XIV-b) is a blood cell, preferably a red blood cell or a platelet, and the compound is preferably 18 In some embodiments, the compound comprises at least an FCM moiety comprising [F], and optionally one or more of CL and OP. 18F] and a BT portion comprising a blood cell, preferably a red blood cell or a platelet, and the compound optionally further comprises an OP and / or a CL. 18 F]-RBC. This embodiment offers certain advantages, including 1) fluorination on or in a non-carbon bearing molecule that can be used to stably radiolabel cells in vivo and demonstrate imaging of cells by PET / SPECT, CT, and / or MRI / MRA, 2) the ability to image the radiolabeled cells by fluorescence, which ensures that the radiolabel does not transfer between cells and can be used to image bleeding by fluorescence, and 3) use in emergency bleeding situations. The compounds described herein with blood cells as the BT moiety provide better resolution, require smaller quantities, and are [ 18 F]-RBCs can be imaged with lower activity, making it more efficient than the corresponding RBC imaging agents (e.g., preclinical chromium and gadolinium RBCs (non-contrast), as well as current clinical SPECT agents [ 99m Tc]-RBCs and [ 99m Tc]-leukocytes (exametazine). In addition, 18 The superior imaging potential of [F]-RBCs can be used to image lesions as small as 1-4 mm in diameter in a 10 mm mouse brain. This non-invasive imaging method advantageously allows for substantially higher resolution imaging than currently available. This improved imaging can be used to image small hemorrhages with higher resolution than current state-of-the-art methods.

[0198] In some embodiments, a method for imaging blood flow in vivo is provided, comprising administering to a subject a compound of formula (I), (Ia), (Ia-1), (II), (III), (IV-a), (IV-b), (Va), (Vb), (X), (Xa), (XI), (XII), (XIII-a), (XIII-b), (XIV-a) or (XIV-b), or a pharma- ceutically acceptable salt thereof, or a subembodiment described herein, or a pharmaceutical composition comprising the same, wherein the BT moiety comprises a cell, preferably a red blood cell or a platelet. Imaging can be used, for example, to assess or monitor the progression of hemorrhage. Hemorrhage can be located in any part of the body, including the brain (e.g., intracerebral hemorrhage, or hemorrhagic or ischemic stroke). Such assessment and monitoring can be particularly important for patients with renal dysfunction, where MRA and CTA are contraindicated. In some embodiments, the method further comprises simultaneous PET and CT imaging on a PET / CT instrument. In some embodiments, the method further includes simultaneous PET / MRI imaging, for example, when a good image of the brain tissue provided by MRI is desirable in situations such as cerebral hemorrhage. In some embodiments, the method is performed intraoperatively, and PET imaging is used to guide the surgeon to the fluorescent probe. This is particularly useful in neurosurgery and otolaryngology, where an endoscopic camera adapted to detect fluorescence is used. In some embodiments, the methods disclosed herein can be applied to imaging traumatic brain injury, intestinal hemorrhage, renal hemorrhage, and internal hemorrhage in emergency situations, where the term "bleeding" can be synonymous with "hemorrhaging." The imaging method can also be used to image perfusion containing thrombi, for example red blood cell perfusion in vascularized composite tissue allografts (VCAs). In particular, changes in blood flow are the earliest indicator of VCA complications. Because the imaging method can detect changes in blood flow, the imaging method can detect complications in VCA and other transplants. The imaging method can also be used to predict intravascular thrombi and point to necrotic areas.

[0199] Imaging methods can also be used, for example, to assess or monitor graft rejection or acceptance for allografts, or more specifically, to image the deep tissues of renal allografts.

[0200] In some embodiments, the imaging method may include simultaneously imaging internal biological tissues by fluorescence imaging using fluorescence imaging techniques known in the art (e.g., F. Leblond et al., Journal of Photochemistry and Photobiology B: Biology, vol. 98 (1), 77-94, January 2010). In particular, the imaging method may be used to image early intravascular thrombus, such as in reconstructive microsurgery, by fluorescence and to image deep tissues of the VCA, for example, by PET / MRI. For example, imaging ( 18 F-fluorophore-blood compositions can be used to monitor clinical graft viability and perfusion at high resolution superficially (in free flaps) or in open surgical sites. Fluorescence imaging can indicate early rejection at the single cell level in skin grafts (FL). Blood cells are optionally radiolabeled with fluorine-18 to generate molecularly (electronically) identical species to the fluorescent probe. PET technology can be used to visualize VCA perfusion in deep graft tissues with PET / CT or PET / MRI devices. Imaging ( 18 F-fluorophore-blood) compositions can be used to generate PET profiles of acute failure, thus predicting impending graft failure and allowing rapid intervention to preserve the allograft. Thus, the fluorophore compositions described herein can prolong graft life and prevent tissue rejection in transplants. Additionally, patients undergoing VCA generally already have an IV catheter in place (for analgesic delivery), thus making IV delivery of labeled blood cells a non-invasive technique.

[0201] In some embodiments, a method of image-guided surgery is provided, comprising administering to a subject a compound of formula (I), (Ia), (Ia-1), (II), (III), (IV-a), (IV-b), (Va), (Vb), (X), (Xa), (XI), (XII), (XIII-a), (XIII-b), (XIV-a) or (XIV-b), or a pharma- ceutically acceptable salt thereof, or a subembodiment described herein, or a pharmaceutical composition comprising same. In some embodiments, the method further comprises (1) performing a PET scan for pre-surgical planning by differentiating disseminated cancer (oligometastatic disease) from localized cancer, (2) performing an MRI or CT scan for further / additional localization for pre-surgical planning, and (3) performing an FL scan for intraoperative surgical guidance. According to this method, the extent of resection is clearly demarcated in three demonstrative procedures: by the surgeon in in vivo observation of unresected margins at the open surgical site and ex vivo in FL / gamma scintillated analysis of resected tissues, and by the pathologist in intraoperative consultation of FL frozen sections. This is made possible by the compounds of the present invention, which provide persistent cancer-specific contrast useful to multiple specialists, including radiologists, urologists, and pathologists, and further provide for further FL histological examination, and FL-assisted cell sorting of resolved cells after surgery.

[0202] Thus, a method of cell imaging is provided that can provide post-operative fluorescence-activated cell sorting (FACS) isolation of cells with selected characteristics with the aid of targeted drugs. In some embodiments, the method provides small molecule or peptide drug labeling in cells by using a compound of formula (I), (Ia), (Ia-1), (II), (III), (IV-a), (IV-b), (Va), (Vb), (X), (Xa), (XI), (XII), (XIII-a), (XIII-b), (XIV-a) or (XIV-b), or a pharma- ceutically acceptable salt thereof.

[0203] In some embodiments, imaging methods are used to assess or monitor the extent or progression of a cancer or precancerous condition, such as by imaging a tumor or precancerous tissue. The cancerous or precancerous tissue imaged may be located in any part of the body, such as the prostate, breast, brain, lung, stomach, intestine, colon, rectum, ovary, cervix, pancreas, kidney, liver, skin, lymph, bone, bladder, or uterus. Cancer may also include the presence of one or more carcinomas, sarcomas, lymphomas, blastomas, or teratomas (germ cell tumors).

[0204] Methods of using the compounds and compositions disclosed herein include, but are not limited to, the following: (i) imaging the tumor via PET imaging, fluorescence imaging and / or optical imaging; (ii) performing drug-targeted tissue biopsies (optionally ultrasound-guided) via PET, fluorescence, and / or optical imaging; (iii) performing surgical procedures (with ultrasound guidance, if necessary) with the aid of PET imaging, fluorescence imaging, and / or optical imaging to identify sentinel lymph nodes, identify specific bleeding sites, or perform surgery on a tumor (e.g., a prostate tumor (e.g., PSMA + tumors), brain tumors (e.g., glioblastoma), head and neck cancer (e.g., squamous cell carcinoma of the head and neck), liver cancer (e.g., hepatocellular carcinoma), lung cancer (e.g., non-small cell lung cancer), colon cancer, colorectal cancer, breast cancer, sarcoma, or ovarian cancer); (iv) Imaging a tissue sample (e.g., a prostate tumor (e.g., PSMA)) via PET imaging, fluorescence imaging, and / or optical imaging. + performing pathological and / or histological analysis of samples obtained from a human tumor, a human ovarian cancer, a human bronchial tumor ... (v) detecting a tumor (e.g., a prostate tumor (e.g., PSMA)) via PET imaging, fluorescence imaging, and / or optical imaging; + determining the condition (e.g., size, location and / or stage) of a tumor (e.g., a glioma), a brain tumor (e.g., glioblastoma), a head and neck cancer (e.g., squamous cell carcinoma of the head and neck), a liver cancer (e.g., hepatocellular carcinoma), a lung cancer (e.g., non-small cell lung cancer), a colon cancer, a colorectal cancer, a breast cancer, a sarcoma, or an ovarian cancer); (vi) detecting a cancer treatment (e.g., a prostate tumor (e.g., PSMA)) via PET imaging, fluorescence imaging, and / or optical imaging; + tumors), brain tumors (e.g., glioblastoma), head and neck cancer (e.g., squamous cell carcinoma of the head and neck), liver cancer (e.g., hepatocellular carcinoma), lung cancer (e.g., non-small cell lung cancer), colon cancer, colorectal cancer, breast cancer, sarcoma, or ovarian cancer); and vii) Imaging cancer surgery (e.g., solid tumors, such as prostate cancer (e.g., PSMA) via PET imaging, fluorescence imaging, and / or optical imaging; + To monitor the progression of cancer (including pre-operative monitoring, post-operative monitoring, and monitoring during surgery) in patients with cancer of the prostate, brain, head and neck, liver, lung, colon, colorectal, breast, sarcoma, or ovarian cancer.

[0205] In some embodiments, the method comprises administering an intravenous mass of 10-10000 umol of a compound of formula (I), (Ia), (Ia-1), (II), (III), (IV-a), (IV-b), (Va), (Vb), (X), (Xa), (XI), (XII), (XIII-a), (XIII-b), (XIV-a) or (XIV-b), or a pharma- ceutically acceptable salt thereof, at least 0-6 hours prior to the PET scan, with an activity in the range of 0.1-30 mCi. The compound is visible on the PET scanner from 0 minutes to 12 hours after injection. Residual co-injected compound is visible by optical / fluorescent means for up to 2 weeks after injection. In some embodiments, the method further comprises a fluorescent guided surgical procedure. Non-positron emitting19 F-containing compositions may be substituted in cases where PET imaging is not desired.

[0206] In some embodiments, the methods include administering a compound of Formula (I), (Ia), (Ia-1), (II), (III), (IV-a), (IV-b), (Va), (Vb), (X), (Xa), (XI), (XII), (XIII-a), (XIII-b), (XIV-a) or (XIV-b), or a pharma- ceutically acceptable salt thereof, with an activity in the range of 3-10 mCi and a mass of less than 100 umol (-100 μg) via intratumoral injection prior to or during a PET scan.

[0207] In one aspect, the method further comprises treatment with a prodrug. In some embodiments, the BT moiety is configured to deliver the compound to a specific biological tissue or site, for example, a tumor site.

[0208] In some embodiments, the present disclosure provides a method for demonstrative imaging after tumor resection surgery, comprising administering to a subject a compound disclosed herein after surgery, and performing postoperative demonstrative imaging on the subject using a suitable technique for detecting the imaging portion of the compound, such as optical, MRI, and / or PET. In some embodiments, the method may further comprise performing postoperative surgery to remove residual tumor tissue where imaging indicates a positive surgical margin.

[0209] In some embodiments, the present disclosure provides a method for image-guided surgery further comprising using a PET scanner in a surgical room, including robot-assisted surgery performed with a PET scanner. According to these embodiments, in the context of treating cancer, the optical signal-to-noise ratio is adjusted to allow computer-assisted identification of surgical margins for resection during surgery or unresected / missed positives after surgery. In further embodiments, computed tomography PET data acquired during surgery is adapted to identify in real time the tumor tissue to be resected, the unresected tumor that must be resected before surgical conclusion, and the lymph nodes involved in the resection. In this context, the PET and optical data are empirical, allowing for improved accuracy compared to standard-of-care surgical procedures performed with non-contrast-guided techniques. In some embodiments, a surgical robot equipped with a camera is adapted for fluorescence data collection. In some embodiments, multiple compounds targeted to different biological sites and containing different fluorescent agents are administered simultaneously to a subject in a method of guided robotic surgery. For example, the multiple compounds may include (i) a first compound having a tumor-targeting BT moiety and an optical probe moiety, such as Cy3, (ii) a second compound having a lymph node-targeting BT moiety and an optical probe moiety, such as Cy5, and (iii) a third compound having a nerve-targeting BT moiety and an optical probe moiety, such as Cy7. In this situation, the method includes administering each of the compounds simultaneously to the subject to help the surgeon identify the cancerous tissue to be removed, the nerves to be avoided, and any lymph nodes, including those infiltrated by the tumor cells.

[0210] In one aspect, the disclosure provides kits for making and / or using any of the aforementioned compounds. The kits may include, for example, a compound of formula (I), (Ia), (Ia-1), (II), (III), (IV-a), (IV-b), (Va), (Vb), (X), (Xa), (XI), (XII), (XIII-a), (XIII-b), (XIV-a) or (XIV-b), or a pharma- ceutically acceptable salt thereof, or a precursor thereof.

[0211] Examples of kit-based preparations include the protocols described below: (i) (preparation from boronic esters) - Wang, Y., An, F., Chan, M., Friedman, B., Rodriguez, EA, Tsien, RY, Aras, 0., and Ting, R. (2017) "18F-positron-emitting / fluorescent labeled erythrocytes allow imaging of internal hemorrhage in a murine intracranial hemorrhage model." J. Cerebral Blood Flow and Metabolism., 37(3), 776-786. PMID: 28054494, (ii) (preparation from 19F-bearing molecules) - Kommidi, H., Guo, H. Nurili, F., Vedvyas, Y.. Jin, MM, McClure, T.,D., Ehdaie, B., Sayman, H., Akin O., Aras, 0., Ting, R. (2018) "18F-positron emitting / trimethine cyanine-fluorescent contrast for image-guided prostate cancer management." J. Med. Chem. 61, 4256-4262, and (iii) Kommidi, H., Guo, H., Chen, N., Kim, D., He, B., Wu, AP, Aras, 0, Ting, R. (2017) "A [18g-positron-emitting, fluorescent, cerebrospinal fluid probe for imaging damage to the brain and spine." Theranostics. 7, 2377-2391. (Cover article) PMID: 28744321. The contents of references (i) to (iii) are incorporated herein by reference in their entireties.

[0212] In an exemplary embodiment, the kit includes a compound of formula (I), (Ia), (Ia-1), (II), (III), (IV-a), (IV-b), (Va), (Vb), (X), (Xa), (XI), (XII), (XIII-a), (XIII-b), (XIV-a) or (XIV-b), or a pharma- ceutically acceptable salt thereof, together with (i) a solution for preparation, including an acidic solution for radiolabeling (i.e., pH=2.0, pyridazine-HCl buffer; note that this can be any acid, e.g., hydrochloric acid), and a solid phase extraction device suitable for adsorbing the labeled analyte, such as a silica-based octadecyl bonded phase (e.g., C18 type cartridge, e.g., manufactured by Waters No. 186005125), for the user to purify their labeled agent. Additional solutions that may be included, if desired, include a solution for purification (e.g., a solution for removing contaminants from the compounds bound on the cartridge [ 18 water in a volume of 20–23 mL to wash out the [F]-fluoride ions), and 4.0 mM HCl solution in ethanol (99%) ([ 18 g-To elute the compound after removal of fluoride ions, and 1 mM phosphate buffered saline x PBS to neutralize the compound. The kit also optionally contains a 0.22 pm filter for drugs that will be administered (e.g., injected) to a patient. The user can then extract the drug from the cyclotron using their own filter. 18 F-fluoride ions must be provided. All solutions are sterile. Optionally, the kit contains only the compound and a C18 cartridge (e.g., Waters No. 186005125) and the user can select the cleaning solution.

[0213] In an exemplary embodiment, the kit includes a precursor compound of formula (I), (Ia), (Ia-1), (II), (III), (IV-a), (IV-b), (Va), (Vb), (X), (Xa), (XI), (XII), (XIII-a), (XIII-b), (XIV-a) or (XIV-b), or a pharma- ceutically acceptable salt thereof, together with (i) a solution for preparation, including an acidic solution for radiolabeling (i.e., pH=2.0, pyridazine-HCl buffer; note that this can be any acid, e.g., hydrochloric acid), and a solid phase extraction device suitable for adsorbing the labeled analyte, e.g., a silica-based octadecyl bonded phase (e.g., C18 type cartridge, e.g., manufactured by Waters No. 186005125), for the user to purify their labeled agent. Additional solutions that may be included, if desired, include a solution for purification (e.g., a solution for removing contaminants from the compounds bound on the cartridge [ 18 water in a volume of 20–23 mL to wash out the [F]-fluoride ions), and 4.0 mM HCl solution in ethanol (99%) ([ 18 g-To elute the compound after removal of fluoride ions, and 1 mM phosphate buffered saline x PBS to neutralize the compound. The kit also optionally contains a 0.22 pm filter for drugs that will be administered (e.g., injected) to a patient. The user can then extract the drug from the cyclotron using their own filter. 18 F-fluoride ions must be provided. All solutions are sterile. Optionally, the kit contains only the compound and a C18 cartridge (e.g., Waters No. 186005125) and the user can select the cleaning solution.

[0214] In some embodiments, the kit comprises the structure [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] or a pharma- ceutically acceptable salt thereof.

[0215] In some embodiments, the precursor is a precursor of compound A-2. In some embodiments, the precursor of compound A-2 is protected (e.g., protected with BOC). In some embodiments, the precursor of compound A-2 is [ka] or a pharma- ceutically acceptable salt thereof.

[0216] In some embodiments, the kit comprises a precursor of compound A-2 as described above in solid powder form, and a solid phase extraction device suitable for adsorbing the labeled analyte, and optionally further comprises one or more sterilization solutions, such as purification, elution, washing, and neutralization solutions.

[0217] In some embodiments, the kit comprises: [ka] or a pharma- ceutically acceptable salt thereof.

[0218] In some embodiments, the kit comprises: [ka] or a pharma- ceutically acceptable salt thereof.

[0219] In some embodiments, the kits include a precursor described herein in solid powder form, and a solid phase extraction device suitable for adsorbing the labeled analyte, and optionally further include one or more sterilization solutions, such as purification, elution, washing, and neutralization solutions.

[0220] In some embodiments, the kit further comprises a metal atom or a metal ion thereof. In some embodiments, the metal atom is a metal in Table 2. In some embodiments, the metal atom is in the ionic form of a metal in Table 2. In some embodiments, the metal atom is 90 Y, 131 I, 177 Lu, 153 Sm, 186 Re, 188 Re, 67 Cu, 212 Pb, 166 Ho, or 47 In some embodiments, the metal atom is 225 Ac, 213 Bi, 212 Bi, 211 At, 212 Pb, 227 Th, or 223 In some embodiments, the metal atom is 125 I, 123 I, 67 Ga, 111 In, 77 Br, and 80m In some embodiments, the metal atom is 90 Y, 131 I, 177 Lu, 153 Sm, 186 Re, 188 Re, 67 Cu, 212 Pb, 166 Ho, or 47 In some embodiments, the metal atom is an ion of 225 Ac, 213 Bi, 212 Bi, 211 At,212 Pb, 227 Th, or 223 In some embodiments, the metal atom is an ion of 125 I, 123 I, 67 Ga, 111 In, 77 Br, and 80m It is a Br ion.

[0221] In some embodiments, the metal atom or ion is provided in a solution. In some embodiments, the metal ion solution may be diluted with a solvent included in the kit. In some embodiments, the metal atom or ion is provided in a salt. In some embodiments, the metal salt may be dispersed in a solvent included in the kit.

[0222] In some embodiments, the kit includes (i) dry compound (e.g., powder or crystalline), (ii) a solution of tin(IV) chloride, and (iii) dry HPLC grade acetonitrile. The user can collect the compound from the cyclotron on their own. 18 This will provide F-fluoride ions. 18 After drying of the F-fluoride, the user would mix all the reagents. In some embodiments, a purification cartridge is not necessary (although one may be used). The user would simply precipitate the compound from water, wash several times with water to remove all fluoride ions, and then resuspend the compound in a PBS-buffered DMSO solution, which would be passed through a 0.22 pm filter in order for the compound to be injected, for example, intratumorally.

[0223] In some embodiments, the kit can include one or more containers selected from the group consisting of bottles, vials, ampoules, blister packs, and syringes. The kit can further include one or more of instructions for use, one or more syringes, one or more applicators, or a sterile solution suitable for reconstituting the compounds or compositions described herein. For example, the kit can include aliquots of these compositions, e.g.18 Mix with acidic water containing F, 18 Instructions for use for providing a PET-visible composition that is loaded with F. In some embodiments, the kit may also include a commercially available column for passing the composition through to remove contaminating fluoride ions prior to administration (e.g., via injection) to a patient.

[0224] In one aspect, a system for an operating room (e.g., a surgical room) is further provided. In some embodiments, the system may include an in-surgery room PET scanner capable of performing confirmatory molecular imaging / treatment, e.g., PET / CT, PET / MRI, or PET / radioisotope. In some embodiments, the system facilitates surgery performed using the PET scanner. In some embodiments, the system provides confirmatory PET imaging, e.g., with a fluorescence endoscope or camera on a surgical robot or on a histopathology cart on the back table.

[0225] The methods, kits, and systems described herein provide evidence-based molecular imaging / therapy before, during, and after surgery that offers advantages over traditional stand-alone PET-only, optical-only, and radioisotope-only imaging agents. EXAMPLES

[0226] Examples are set forth below for illustrative purposes and to describe the best mode of the invention at the time of the invention, however, the scope of the invention should not be limited in any way by the examples set forth herein. Example 1 Synthesis of exemplary compounds of formula I depicted in Figures 3A-3C

[0227] Reagents and conditions a) 1 equivalent of 6-bromohexanoic acid, p-NH2-Bn-DOTA-tetra(t-Bu ester), HOBt (hydroxybenzotriazole), 2.5 equivalents of pyridine, 4.0 equivalents of EDC.HCl (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride), DMF (dimethylformamide), RT (room temperature), N2 (nitrogen atmosphere), 6 hours, b) 1.2 equivalents of 2-(dimethylamino)ethylamine, t-BuOK (tert-butyl alcohol, potassium salt), MeOH (sodium hydroxide), room temperature, 2 hours; c) 1.0 equivalent of CY3.18.OH (trimethine cyanine), 1.0 equivalent of ACUPA ((S)-2-(3-((S)-5-amino-1-carboxypentyl)ureido)pentanedioic acid), 2.5 equivalents of HOBt, 2.5 equivalents of pyridine, 4.0 equivalents of EDC.HCl, DMF, RT, N2, d) 1.0 eq. of 2, 1.0 eq. of 3, 2.5 eq. of HOBt, 2.5 eq. of pyridine, 4.0 eq. of EDC.HCl, DMF, RT, N2, e) (1) 1.1 equivalents of bromomethylboronic acid pinacol ester, DIPEA (N,N-diisopropylethylamine), DMF / THF (2:1), room temperature, 1 hour, (2) 3M KHF2, 1M HCl, 0°C to room temperature, 1 hour, f) 1) 0.5 mL TFA, 2 hours.

[0228] Metal insertion: incubation of metal chloride salts in 100 mM ammonium carbonate, pH 7.5. Radiolabeling: (if required): 1 M pyridazine-HCl, pH = 2.5, 50 mCi of aqueous [18F]-fluoride ion (specific concentration >1.5 Ci / mL), 80-90 °C. Synthesis of tert-butyl 2,2',2'',2''''-(2-(4-(7-bromoheptanamido)benzyl)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetraacetate (1)

[0229] To a solution of 6-bromohexanoic acid (approximately 100 μmol) in 4 mL of dry DMF in an oven-dried 5 mL round-bottom flask, p-NH2-Bn-DOTA-tetra(t-Bu ester) (100 μmol), 1-hydroxybenzotriazole (33 mg, 300 μmol) and 18 μL of pyridine were added, followed by initiation of the condensation with N-3(-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC.HCl) (25 mg, 133 μmol, Fluka 03450). The reaction was allowed to proceed for 5 h at 27 °C under magnetic stirring under ambient atmosphere, after which a new peak corresponding to 1 was observed by UPLC / MS. The resulting solution was diluted with DMF (5 mL) and the mixture was loaded onto a preparative HPLC column. Compound 4 was isolated using a HO:ACN (0.05% TFA) elution gradient at a flow rate of 12 mL / min. The fractions containing 1 were lyophilized in vacuum to give pure (O t Bu)DOTA-Cy3-tert-amine 1 was obtained as a white powder. Synthesis of tert-butyl 2,2',2'',2''''-(2-(4-(7-(2-(dimethylamino)ethylamino)heptanamido)benzyl)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetraacetate (2)

[0230] To a solution of 1 (approximately 100 μmol) in 4 mL of methanol, 1.2 equivalents of potassium t-butoxide are added dropwise. Then, 1.2 equivalents of 2-(dimethylamino)ethylamine are added. The reaction is allowed to proceed at room temperature under ambient atmosphere and magnetic stirring for 5 h, after which a new peak corresponding to 2 is observed by UPLC / MS. The resulting solution is diluted with DMF (5 mL) and the mixture is loaded onto a preparative HPLC column. Compound 2 is isolated using a HO:ACN (0.05% TFA) elution gradient at a flow rate of 12 mL / min. The fractions containing 2 are lyophilized in vacuum to give amine 2 as a white powder. Synthesis of tert-butyl 2,2',2''-(2-(4-(7-(N-(2-(dimethylamino)ethyl)amido)heptanamido)benzyl)-10-(2-isopropoxy-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate-Cy3-(R)-di-tert-butyl 2-(3-((S)-6-acetamido-1-tert-butoxy-1-oxohexan-2-yl)ureido)pentanedioate tBu)DOTA-Cy3-tert-amine (4)

[0231] In an oven-dried 5 mL round-bottom flask, a magnetically stirred solution of CY3.18.OH (25 mg, 34 μmol, synthesis adapted from Mujumdar et al., 1993) in 2 mL of dry DMF is mixed with (S)-di-tert-butyl-2-(3-((S)-6-amino-1-(tert-butoxy)-1-oxohexan-2-yl)ureido)pentanedioate 1 (17 mg, 34 μmol, Astatech, CAS 1025796-31-9, catalogue no. W11493), 1-hydroxybenzotriazole (12 mg, 87 μmol) and 7 μL of pyridine, followed by initiation of the condensation with EDCI (42 mg, 217 μmol). The reaction is allowed to proceed at 27 °C for 6 h, after which the monosubstituted Cy3-amide intermediate (compound 3) is observable by UPLC / MS. At the 5th hour, compound 4 and additional EDCI (42 mg, 217 μmol, Fluka 03450) are added to the rbf and the reaction is allowed to proceed for an additional 4 hours at 28° C. The resulting solution is diluted with DMF (4 mL) and the mixture is loaded onto a preparative HPLC column. Compound 5 is isolated using a 50 min elution gradient of HO:ACN (0.05% TFA) at a flow rate of 12 mL / min. Fractions containing 5 are lyophilized in vacuum to give a pure pink powder. Synthesis of BF3-DOTA-Cy3-PSMA(OtBu) (5)

[0232] To a magnetically stirred solution of 4 (9.9 μmol) in dimethylformamide (DMF) at room temperature, 2.0 mL of neat diisopropyl ethylamine (2 μL, 9.9 μmol) was added, followed by (bromomethyl)boronic acid pinacol ester (2.6 mg, 12.0 μmol). The reaction was allowed to proceed at RT for 2.0 h or until complete consumption of starting material and formation of the desired N-alkylated product was observed by UPLC-MS. The boronate was converted to the trifluoroborate without further purification. A 1 M solution of potassium bifluoride (KHF2, 20 μL) followed by 3 M hydrochloric acid (HCl, 10 μL) is added to the reaction pot at 0 °C. The reaction is stirred at room temperature under ambient atmosphere for 1 h. The formation of 5 is confirmed by UPLC-MS. The resulting solution was quenched with 5 μL of 28% NH4OH, filtered, washed with DMF (1.5 mL), and purified by preparative HPLC using a 50 min elution gradient of HO:ACN (0.05% TFA) at a flow rate of 12 mL / min. 5 was eluted using a linear gradient of increasing ACN from 10% to 70% between 0-40 min, followed by a linear gradient of increasing ACN from 70% to 90% between 40-50 min. Fractions containing the desired product were lyophilized in vacuo to give pure (BOC)-protected 5 as a pink powder. Isolated yield. Synthesis of BF3-DOTA-Cy3-PSMA (6)

[0233] Neat trifluoroacetic acid (TFA) (1.0 mL) was added to a stirred solution of 5 (5.0 μmol) at 0° C. Under continuous stirring, the reaction was allowed to warm to room temperature (25° C.) over 1 h. Clean conversion of the BOC (tert-butyloxycarbonyl) protected acid to the corresponding acid was observed by UPLC / MS. TFA was removed from the mixture under vacuum. The resulting solid was dissolved in DMF (1.0 mL) and purified by preparative HPLC. The fractions containing the desired product were lyophilized in vacuum to give chemically pure 6 as a pink powder. Consideration

[0234] In Figures 3A-3C, the tert-butyloxycarbonyl or tert-butoxycarbonyl protecting group (also called "BOC" group), designated in the diagram as "O-tBu", should remain on the chelator until step f to avoid self-reaction between the amine and carboxyl groups of the chelator. Failure to incorporate the acid-BOC protection may cause the reaction scheme to fail. BOC protection is preferred over other protecting groups here due to the presence of the organic fluorophore. The organic fluorophore is reasonably chemically reactive due to the presence of the extended pi-conjugation. Protecting groups that are base and platinum-hydrogen labile destroy the organic fluorophore by either reducing it or reacting irreversibly with it. In addition, other protecting groups may prevent the use of product 2, a reagent that exploits the reactive properties of secondary and tertiary amines.

[0235] Care should be taken that the reagent does not contain divalent or trivalent countercations, the presence of which may cause irreversible reactions with the chelator (chelation) and / or deprotection of the OtBu-protected chelator.

[0236] Compound 2, generated after steps a and b, is a key intermediate. Compound 2 contains both unhindered (dimethyl-substituted) tertiary and secondary amines. The presence of unhindered tertiary amines on product 4 allows our molecule to bear fluoride after site-specific halomethylboronic acid pinacolatoate reaction and subsequent fluoride treatment (step e). The secondary amine on compound 2 allows compound 2 to undergo site-specific amide formation in step d. This strategic use of both tertiary and secondary amines on compound 2 prevents side reactions in steps d and e. In other words, dimethyl-substituted tertiary amines do not undergo amide formation in step d, while the formed N-alkylamides do not undergo reaction with halomethylboronic acid pinacolatoate in step e. In addition, tertiary and secondary amines do not react with chelators or deprotect. Tertiary and secondary amines undergo few side reactions in step d if the biological targeting ligand or fluorophore contains the requisite reactive acid / amine / nucleophile. Compound 2 is also required to effect site-specific reactions in steps d and e.

[0237] To increase the yield, step d can be carried out in a one-pot two-step reaction. This avoids the possibility of reduced yield from isolation of acid-Cy3-ACUPA after step c. In particular, the secondary amine (i.e., the product of reaction b) must be the limiting reagent. This reagent must follow the post-ACUPA reaction in the second step of the two-step reaction of step d because the chelator-secondary amine is expensive and / or time-consuming to make.

[0238] In step c), ACUPA or the substituted biological targeting ligand reagent must contain only a single reactive amine. All other essential amines and acids on the biological entity should be chemically protected.

[0239] Ideally, the reaction of the biological targeting ligand in step c should satisfy the following conditions: a) an acid-labile protecting group is used (OtBu is preferred) since alternative bases, nucleophiles, strong electrophiles and platinum-hydrogen deprotection strategies would destroy the organic fluorophore, b) the molecule should contain a single reactive amine to prevent over-reaction of the bis-acid, CY3 (2-fold amide formation) (step c), and c) precise stoichiometric control must be exerted in step c to prevent over-reaction of the bis-acid, CY3.

[0240] The synthesis of compound 4 (FIG. 3C) is set up by using compound 2. Compound 4 contains a single unprotected tertiary amine, i.e., only one reactive tertiary amine. The generation of a molecule bearing this single unhindered (dimethyl-substituted) tertiary amine may be important for high-yield site-specific trifluoroborate functionalization in step e. In addition, compound 4 is not protected and does not bear additional unprotected secondary or primary amines or acids that may interfere with the site-specific reaction in step e.

[0241] In FIG. 3C, the secondary amine, compound 4, can be reacted with a halomethylboronic acid pinacol ester to give a boron pinacolate, which can then be treated with potassium bifluoride ion to give the quaternary amine ( 19 F, or 18 F)-trifluoroborate is obtained. Potassium bifluoride can be used to convert boron pinacolate to trifluoroborate, since hydrogen fluoride or other fluoro acids / electrophiles / nucleophiles can result in OtBu deprotection / destruction of the fluorophore.

[0242] Compound 5 is the most preferred product for long-term bulk precursor pharmaceutical active ingredient storage, but compound 4 can also undergo long-term storage. Deprotection of compound 5 should be carried out using trifluoroacetic acid. The use of other fluoro acids may destroy the organic fluorophore.

[0243] After the TFA deprotection in step f, the lifetime of compound 6 (compound A-2 in paragraph

[0120] ) varies depending on whether the chelator is a radioactive metal (for 177Lu or 225Ac-alpha treatment) or a non-radioactive metal ( 175 The potential of BF3 is very limited unless loaded with the desired metal, whether Lu or Gd - for fluorescence-guided surgery or 18F PET imaging. If the chelator in compound 6 is not loaded immediately, fluoride removal / decomposition of BF3 may occur. Compound 6 after metal loading becomes less reactive and can be a precursor to 19F / 18F substitution for PET imaging or can be used in its non-radioactive form for fluorescence imaging.

[0244] PET radiolabel ( 19 F / 18 F) can occur either before, during or after metal chelation, however the chelator in compound 6 should be rapidly loaded with the metal to avoid fluoride removal / decomposition. As can be seen from this example, radiolabeled moieties, e.g. 19 F / 18 The synthesis of compounds combining 18F with an optical imaging agent, such as an organic fluorophore, and a chelator, such as DOTA, is not trivial. To the inventors' knowledge, such multimodal (optical / PET / RIT) compounds have not been described or synthesized prior to the present invention. Conventional methods for 18F radiolabeling, such as fluoride-carbon substitution, would be disruptive to all currently FDA-approved fluorophores. Example 2 Synthesis of compound A-23

[0245] S-2-(4-aminobenzyl)-1,4,7,10-tetraazacyclododecane tetra-tert-butyl acetate and (S)-di-tert-butyl 2-(3-((S)-6-amino-1-(tert-butoxy)-1-oxohexan-2-yl)ureido)pentanedioate were purchased.

[0246] HPLC-MS Conditions: Analytical reverse phase HPLC-MS was performed on an Agilent 1200 HPLC Prep / Analytical LCMS system. All analytical HPLC were performed using a10-90 (water-acetonitrile), 20 min (or 10 min for A-23-Int1 only) gradient, where both solvents contained 0.05% trifluoroacetic acid. Analytes were run at a flow rate of 1 mL / min through a Phenomenex Luna, 10 um, C18(2), 100A, 250 x 4.6 mm column (P / No. 00G-4253-E0, SN H21-218267). Analysis was performed using an Agilent G7165A Multiwavelength detector placed upstream from an in-line Agilent G6125B mass spectrometer. Wavelengths were as specified. [ka]

[0247] A 50 mL round bottom flask was charged with a magnetic stir bar and glacial acetic acid (6 ml, 104 mmol). 3-Methyl-2-butanone (3.4 ml, 31 mmol) was added to the flask, after which the flask was transferred to a hot plate and magnetically stirred. 4-Hydrazinylbenzenesulfonic acid (2 g, 10.2 mmol) was added to the stirred solution and the reaction was heated to 110 °C. The reaction was allowed to proceed at 110 °C for 24-72 h, during which time a change from pink to deep purple was observed. The resulting solution was diluted with 20 mL of water and then shell frozen at -26 °C. The frozen reaction was lyophilized in vacuum to afford A-23-Int1 as a hygroscopic purple solid (~90% pure at 350 nm by HPLC). HPLC-MS: 239.9 (MH+), analytical HPLC retention time = 13.9 min (210 nm). [ka]

[0248] A 50 mL round bottom flask was charged with a magnetic stir bar and A-23-Int1 (2.4 g, 10.2 mmol). 1,2 dichlorobenzene (5.6 mL) and 6-bromohexanoic acid (5 mL) were added to the vial, respectively. The vial was transferred to a magnetic stirrer and saturated potassium hydroxide-isopropyl alcohol solution (5 mL, 2.6 M) was added to the solution. The reaction was heated to 110° C. and allowed to proceed for 48 hours, whereupon the reaction was cooled to room temperature resulting in a biphasic mixture consisting of a dense purple oil containing the product and a supernatant. The supernatant was decanted and 5 ml of water was added to the oil. Titration of the oil with water gave a solution suitable for preparative HPLC (10 μm C18(2) 250×21.2 mm 100A preparative column, using an elution gradient of 0% to 25% HO / ACN (0.05% TFA) in 20 min at a flow rate of 15 mL / min) to give 0.67 g of A-23-Int2 (>95% purity at 250 nm by HPLC). HPLC-MS: 354.1 (MH+), analytical HPLC retention time = 13.1 min (210 nm). [ka]

[0249] 1-(5-carboxypentyl)-2-((E)-3-((E)-1-(5-carboxypentyl)-3,3-dimethyl-5-sulfoindolin-2-ylidene)prop-1-en-1-yl)-3,3-dimethyl-5-sulfo-3H-indol-1-ium salt (A-23-Int3) was synthesized from A-23-Int2 and triethoxymethane. A 5 mL vial was charged with A-23-Int2 (0.67 g, 2.8 mmol). N,N-Dimethylformamide (2 mL) was added to give fully solubilized A-23-Int2. Pyridine (1.33 mL, 16.5 mmol), and triethyl orthoformate (1.33 mL, 8 mmol) were then added to the mixture. The vial was transferred to a stir plate / heater at 110 °C. The reaction was heated at 110 °C for 2 h. A color change from dark purple to an intense bright pink was observed within minutes of heating. After 2 h, the reaction was separated on a 10 μm C18(2) 250 x 21.2 mm 100A preparative column using an elution gradient of 10% to 90% HO / ACN (0.05% TFA) in 20 min at a flow rate of 15 mL / min to give A-23-Int3 (0.42 g, >89% pure at 550 nm by HPLC). HPLC-MS: 717.0 (M+), analytical HPLC retention time = 9.4 min (250 nm). [ka]

[0250] 1-(6-(((5S,9R)-12-(tert-butoxy)-5,9-bis(tert-butoxycarbonyl)-7,12-dioxododecyl)amino)-6-oxohexyl)-2-((E)-3-((E)-3,3-dimethyl-1-(6-oxo-6-((4-((1,4,7,10-tetrakis(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecan-2-yl)methyl)phenyl)amino)hexyl)-5-sulfoindolin-2-ylidene)prop-1-en-1-yl)-3,3-dimethyl-5-sulfo-3H-indol-1-ium salt (A-23-Int4) was synthesized from A-23-Int3. S-2-(4-aminobenzyl)-1,4,7,10-tetraazacyclododecane tetra-tert-butyl acetate (5 mg, 6 μmol), N,N-dimethylformamide (140 μL), A-23-Int3 (6.2 mg, 8 μmol), 1-hydroxybenzotriazole (6 mg, 43 μmol), and pyridine (10 μL) were added, followed by initiation of the condensation with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (18 mg, 94 μmol). The condensation reaction was allowed to proceed at room temperature for approximately 24 hours. After 24 hours, (S)-di-tert-butyl 2-(3-((S)-6-amino-1-(tert-butoxy)-1-oxohexan-2-yl)ureido)pentanedioate (6 mg, 12.3 μmol) and additional 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (18 mg, 94 μmol) were added to the reaction mixture. After allowing the reaction to stand at room temperature for 72 hours, the reaction was diluted with N,N-dimethylformamide (300 μL) and the mixture was loaded onto a preparative HPLC. HPLC separation was performed on a 10 μm C18(2) 250×21.2 mm 100A preparative column using an elution gradient of 10% to 90% HO / ACN (0.05% TFA) in 20 minutes at a flow rate of 15 mL / min. HPLC-MS: 1902.4 (M+), analytical HPLC retention time = 17.5 min (250 nm). [ka]

[0251] Synthesis of compound A-23. Powdered A-23-Int4 (approximately 1 mg) was weighed and added to an empty 1.5 mL vial. A 200 μL volume of trifluoroacetic acid was added and the reaction was allowed to proceed for 2 hours. After 2 hours, the reaction was diluted with 1 mL of HPLC grade water. The entire reaction was frozen and lyophilized in vacuum to give compound A-23 trifluoroacetate as a pink solid. HPLC-MS: 1509 (M+), analytical HPLC retention time = 7.84 min (550 nm). Example 3 Synthesis of compound A-22-Int4

[0252] Analytical HPLC-MS conditions were as described in Example 2.

[0253] S-2-(4-aminobenzyl)-1,4,7,10-tetraazacyclododecane tetra-tert-butyl acetate and (S)-di-tert-butyl 2-(3-((S)-6-amino-1-(tert-butoxy)-1-oxohexan-2-yl)ureido)pentanedioate were purchased. N-propargyl-N,N-dimethylammoniomethyl trifluoroborate was synthesized according to Angew. Chem. Int. Ed. 2014, 53, 11876. [ka]

[0254] Tetra-tert-butyl 2,2',2'',2''''-(2-(4-((S)-2-amino-5-azidopentanamido)benzyl)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetraacetate (A-22-Int2) was converted to tetra-tert-butyl 2,2',2'',2'''-(2-(4-((S)-2-(((9H-fluoren-9-yl)methyl)amino)-5-azidopentanamido)benzyl)-1,4,7,10-tetra A-22-Int1 was synthesized by Fmoc deprotection of (S)-2-(((9H-fluoren-9-yl)methyl)amino)-5-azidopentanoic acid and tetra-tert-butyl 2,2',2'',2'''-(2-(4-aminobenzyl)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetraacetate. To an empty 1.5 mL vial, S-2-(4-aminobenzyl)-1,4,7,10-tetraazacyclododecane tetra-tert-butyl acetate (25.5 mg, 30 μmol), N,N-dimethylformamide (350 μL), S-5 azido-2-(Fmoc-amino)pentanoic acid (16.9 mg, 44 μmol), 1-hydroxybenzotriazole (6 mg, 157 μmol), and pyridine (37 μL) were added, followed by initiation of the condensation with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (75 mg, 390 μmol). As the reaction proceeded, the resulting reaction slurry became completely soluble. The reaction was allowed to stand at room temperature for 24 hours, after which 300 μL of 20% piperidine, i.e., N,N-dimethylformamide fluorenylmethyloxycarbonyl (Fmoc) deprotection solution, was added. After Fmoc deprotection proceeded for 3 h at room temperature, the reaction was diluted with N,N-dimethylformamide (300 μL) and the mixture was loaded onto a preparative HPLC. HPLC separation was performed on a 10 μm C18(2) 250 × 21.2 mm 100A preparative column using an elution gradient of 10% to 90% HO / ACN (0.05% TFA) in 20 min at a flow rate of 15 mL / min.HPLC-MS: 873.4 (M+), HPLC retention time for analysis = 9.7 minutes (250 nm).

Chem.

[0255] 2-((E)-3-((E)-1-(6-(((2S)-5-azido-1-oxo-1-((4-((1,4,7,10-tetrakis(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecan-2-yl)methyl)phenyl)amino)pentan-2-yl)amino)-6-oxohexyl)-3,3-dimethyl-5-sulfoindolin-2-ylidene)prop-1-en-1-yl)-1-(6-(((5S,9R )-12-(tert-butoxy)-5,9-bis(tert-butoxycarbonyl)-7,12-dioxododecyl)amino)-6-oxohexyl)-3,3-dimethyl-5-sulfo-3H-indol-1-ium salt (A-22-Int3) was synthesized from A-22-Int2 and A-23-Int3, followed by coupling with tri-tert-butyl (3R,7S)-11-amino-5-oxoundecane-1,3,7-tricarboxylate. To an empty 1.5 mL vial was added A-22-Int2 (approximately 1 mg, 311 mAu at 210 nm) in 200 μL N,N-dimethylformamide, A-23-Int3 (10 mg, 13.3 μmol) in 200 μL N,N-dimethylformamide, 1-hydroxybenzotriazole (6 mg, 43 μmol), and 10 μL pyridine, followed by initiation of condensation with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (18 mg, 94 μmol). The condensation reaction was allowed to proceed for 5 h at room temperature. After 5 hours, 6 mg (12.3 μmol) of (S)-di-tert-butyl 2-(3-((S)-6-amino-1-(tert-butoxy)-1-oxohexan-2-yl)ureido)pentanedioate and additional 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (27 mg, 141 μmol) were added to the reaction mixture. After allowing the reaction to stand at room temperature for 48 hours, the reaction was diluted with N,N-dimethylformamide (300 μL) and the mixture was loaded onto a preparative HPLC. HPLC separation was performed on a 10um C18(2) 250×21.2 mm 100A preparative column using an elution gradient of 10% to 90% HO / ACN (0.05% TFA) in 20 minutes at a flow rate of 15 mL / min. HPLC-MS: 1020.1 (M2+), retention time = 18.0 min (250 nm). [ka]

[0256] ((((1-((4S)-4-(6-((E)-2-((E)-3-(1-(6-(((5S,9R)-12-(tert-butoxy)-5,9-bis(tert-butoxycarbonyl)-7,12-dioxododecyl)amino)-6-oxohexyl)-3,3-dimethyl-5-sulfo-3H-indol-1-ium-2-yl)allylidene)-3,3-dimethyl-5-sulfoindolin-1-yl)hex Sanamido)-5-oxo-5-((4-((1,4,7,10-tetrakis(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecan-2-yl)methyl)phenyl)amino)pentyl)-1H-1,2,3-triazol-4-yl)methyl)dimethylammonio)methyl)-trifluoroborate (A-22-Int4) was synthesized from A-22-Int3. To an empty 1.5 mL vial was added A-22-Int3 (approximately 1 mg, 311 mAu at 210 nm), N-propargyl-N,N-dimethylammoniomethyl trifluoroborate (3 mg, 18 mg) and ascorbic acid (3.9 mg, 22 μmol) in 200 μL of N,N-dimethylformamide. Copper sulfate solution was prepared by dissolving copper(II) sulfate pentahydrate (1 mg, 4 μmol) in water (20 μL) in a second separate 1.5 mL vial. The entire copper sulfate solution was transferred to the first vial to initiate the reaction. The reaction was allowed to stand at room temperature for 16 hours. After 16 hours, the reaction was diluted with N,N-dimethylformamide (1.3 mL) and the mixture was loaded onto a preparative HPLC. HPLC separation was performed on a 10um C18(2) 250×21.2 mm 100A preparative column using an elution gradient of 10% to 90% H2O / ACN (0.05% TFA) in 20 minutes at a flow rate of 15 mL / min. HPLC-MS: 1102.5 (M2+), retention time = 16.0 min (550 nm).

[0257] Compound A-22-Int4 can serve as a precursor for compound A-22. Example 4 Synthesis of metal chelating compounds A-22 and A-23

[0258] In order to use compounds A-22-Int4 and A-23-Int4, they must first be placed in a state in which they can trap metal ions, i.e., converted to compounds A-22 and A-23, respectively, by removing the t-butyl ester protecting group.

[0259] For example, compound A-22-Int4 is treated with neat trifluoroacetic acid (TFA) for 5 minutes. The resulting compound A-22 is isolated by freezing (-20°C) and then lyophilized to obtain the desired compound as a dry powder.

[0260] Two methods can be used to load metal ions into compound A-22 or A-23: (1) an aqueous solution containing metal halides can be added directly to the aforementioned trifluoroacetic acid solution used to make compound A-22 or A-23, (2) the metal is loaded when the lyophilized product is resuspended in water or buffered saline. Lyophilized powder containing compound A-22 or A-23 can be resuspended in water or phosphate buffered saline containing metal halides. Metal chelation is complete within 5 minutes of incubation. To remove excess metal, the final metal-containing solution is filtered through a metal chelating column or a cation exchange column to remove free metal.

[0261] Compounds A-22 and A-23 are loaded with metals, which can be gadolinium, gallium, lutetium, or actinium. Any metal chelating compound can be used for fluorescence imaging, but only metal chelating compound A-22 can be used for PET imaging. Stable non-radioactive metals (Gd, Lu-175) are preferred for PET and fluorescence imaging, while Lu-177 and Ac-225 are preferred for radioisotope therapy. Example 5 Medical Uses of Metal Chelating Compounds A-22 and A-23 Fluorescence image-guided surgery (FIGS) or fluorescent histopathology

[0262] Metal chelating compounds A-22 and A-23 can be used in fluorescence image-guided surgery (FIGS) and fluorescent histopathology. Surgeons prefer to work with inert, non-radioactive metals (M), such as 175-Lu. Metal chelating compounds A-22 and A-23 are diluted in 1 mM phosphate-buffered saline (1xPBS) before injection and filtered through a 0.22 μm filter. The resulting filtrate at pH 7.4 is injected intravenously. PET imaging

[0263] Radiolabeling of metal-chelating compound A-22 is carried out in one step under aqueous acidic pH conditions (pH = 2.0, pyridazine-HCl buffer, 10 μL) and proceeds rapidly (10-15 min) at elevated temperature (80-90 °C). Removal of unreacted [18F]-fluoride ions is performed by passing the radiolabeling mixture of metal-chelating compound A-22 through a prewashed (5 mL, deionized water) C18 cartridge (Waters number 186005125). A 20-23 mL volume of water is used to wash contaminating [18F]-fluoride ions from the cartridge. [18F]-metal-chelating compound A-22 bound to the cartridge is eluted with 4.0 mM HCl in ethanol (99%). The resulting [18F]-metal chelating compound A-22 in acidic ethanol is immediately diluted 10-fold with 1 mM phosphate-buffered saline (1x PBS) and filtered through a 0.22 μm filter. The resulting filtrate at pH 7.4 is injected intravenously through the cephalic vein in 3-5 mL solution, allowing a mean time of 73 ± 27 min to pass between injection and imaging acquisition. Gd-enhanced MRI imaging

[0264] Gd-labeled compound A-22 or A-23 can be used in high mass MRI imaging. Gd-labeled compound A-22 or A-23 is diluted with 1 mM phosphate buffered saline (1xPBS) and filtered through a 0.22μm filter. The resulting pH 7.4 filtrate is injected intravenously via the cephalic vein. Radiation therapy

[0265] Metal-labeled compounds A-22 and A-23 (metals are 177 Lu or 225 Ac) can be used in radioisotope therapy (RIT). The metal-labeled compound is diluted with 1 mM phosphate buffered saline (1×PBS) and filtered through a 0.22 μm filter. The resulting filtrate, pH 7.4, is injected intravenously via the cephalic vein.

[0266] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention as described herein which equivalents are intended to be encompassed by the following claims.

[0267] All references mentioned in this specification are incorporated by reference in their entirety for all purposes to the same extent as if each individual publication or patent or patent application was specifically and individually indicated to be incorporated by reference in its entirety for all purposes.

[0268] The present invention should not be limited in scope by the specific embodiments described herein. Indeed, various modifications of the present invention in addition to those described herein will become apparent to those skilled in the art from the foregoing description and accompanying figures. Such modifications are intended to be included within the scope of the appended claims.

Claims

1. A compound, or a pharmaceutically acceptable salt thereof, (i) Fluorine atom supported portion (FCM), (ii) Chelate ligand moiety (CL), (iii) Optical probe portion (OP), and (iv) Biological targeting moiety (BT) Includes, One or more of the parts of (i) to (iv) are attached, joined, or connected by one or more linkers selected from L1, L2, L3, L4, L5, L6 and L7, L 1 is a bond, -L 1A , -L 1A L 1B -, -L 1A L 1B -L 1C -, -L 1A C(O)NR 11 L 1B -, -L 1A NR 11 L 1B -, -L 1A C(O)L 1B -, -L 1A C(O)OL 1B -, -L 1A OC(O)L 1B -, -L 1A (OL 1B ) n1 -, -L 1A NR 11 C(O)L 1B -, -L 1A NR 11 C(O)OL 1B -, or -L 1A NR 11 (OL 1B ) n1 -, L 2 is a bond, -L 2A , -L 2A L 2B -, -L 2A L 2B -L 2C -, -L 2A C(O)NR 12 L 2B -, -L 2A NR 12 L 2B -, -L 2A C(O)L 2B -, -L 2A C(O)OL 2B -, -L 2A OC(O)L 2B -, -L 2A (OL 2B ) n2 -, -L 2A NR 12 C(O)L 2B -, -L 2A NR 12 C(O)OL 2B -, or -L 2A NR 12 (OL 2B ) n2 -, L 3 is a bond, -L 3A , -L 3A L 3B -, -L 3A L 3B -L 3C -, -L 3A C(O)NR 13 L 3B -, -L 3A NR 13 L 3B -, -L 3A C(O)L 3B -, -L 3A C(O)OL 3B -, -L 3A OC(O)L 3B -, -L 3A (OL 3B) n3 -, -L 3A NR 13 C(O)L 3B -, -L 3A NR 13 C(O)OL 3B -, or -L 3A NR 13 (OL 3B) n3 -, L 4 is a bond, -L 4A , -L 4A L 4B -, -L 4A L 4B -L 4C -, -L 4A C(O)NR 14 L 4B -, -L 4A NR 14 L 4B -, -L 4A C(O)L 4B -, -L 4A C(O)OL 4B -, -L 4A OC(O)L 4B -, -L 4A (OL 4B ) n4 -, -L 4A NR 14 C(O)L 4B -, -L 4A NR 14 C(O)OL 4B -, or -L 4A NR 14 (OL 4B ) n4 -, L 5 is, 【Chemistry 100】 And, L6 is, 【Chemistry 101】 【Chemical Engineering 102】 And, L 7 is, 【Chemistry 103】 And, Each of L1A, L1B, L1C, L2A, L2B, L2C, L3A, L3B, L3C, L4A, L4B, L4C, L5A, L5B, L6A, L6B, L7A, and L7B is independently a bonded, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene. Each of R11, R12, R13, R14, R15, and R16 is independently hydrogen and an unsubstituted alkyl group. Each of n1, n2, n3, n4, n5, n6, and n7 is an integer between 0 and 20, independently. A compound, or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, further comprising a metal ion bound to the chelated portion (CL).

3. The FCM is 【Chemical 104】 A compound according to claim 1, or a pharmaceutically acceptable salt thereof, comprising the above.

4. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the OP comprises one or more fluorophores selected from trimethin cyanine (Cy3), pentamethin cyanine (Cy5), heptamethin cyanine (Cy7), rhodamine, Evans blue (6,6'-{(3,3'-dimethyl[1,1'-biphenyl]-4,4'-diyl)bis[diazen-2,1-diyl]}bis(tetrasodium salt of 4-amino-5-hydroxynaphthalene-1,3-disulfonate), and isosulfan blue (lymphazlin).

5. The BT is 【Chemistry 105】 【Chemistry 106】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

6. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein CL comprises one or more portions selected from dodecanetetraacetic acid (DOTA), nitro-DOTA, 4-aminophenylethyl-1,4,7,10-tetraazacyclodecane-N,N',N'',N'''-tetraacetic acid (PA-DOTA), diethylenetriaminepentaacetic acid (DTPA), (2-[4,7-bis(carboxymethyl)-1,4,7-triazonan-1-yl]acetic acid)NOTA, (triethylenetetramine)TETA, desferrioxamine, (ethylenediaminetetraacetic acid)EDTA, and penicillamine.

7. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the metal ion is a cation of a metal selected from 177 Lu, 225 Ac, Ga, Cu, Sm, Ra, Y, Pd, Ir, and Pb.

8. The compound is 【Chemistry 108】 A compound according to claim 1 having the structure, or a pharmaceutically acceptable salt thereof.

9. Structure 【Chemistry 111】 【Chemistry 112】 【Chemistry 113】 【Chemistry 114】 【Chemical 115】 【Chemistry 116】 【Chemistry 117】 【Chemistry 118】 or 【Chemical 119】 A compound according to claim 1, or a pharmaceutically acceptable salt thereof, having the above.

10. Structure 【Chemical 120】 or 【Chemistry 121】 A compound according to claim 1, or a pharmaceutically acceptable salt thereof, having the above.

11. The compound is 【Chemistry 122】 【Chemical 123】 【Chemistry 124】 【Chemistry 125】 【Chemistry 126】 The compound according to claim 8, or a pharmaceutically acceptable salt thereof.

12. The compound is 【Chemistry 130】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

13. The compound is 【Chemistry 135】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

14. The compound is 【Chemistry 137】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

15. The compound is 【Chemistry 138】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

16. The compound is 【Chemistry 143】 【Chemistry 144】 【Chemistry 145】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

17. A pharmaceutical composition comprising the compound described in Claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.

18. A composition for use in a method for internal imaging of biological tissue in a subject, wherein the composition comprises the compound described in Claim 1 or a pharmaceutically acceptable salt thereof, and the method is (i) Administering the composition to the subject, (ii) Imaging the biological tissue using a method comprising at least one of positron emission tomography (PET), single-photon emission computed tomography (SPECT), magnetic resonance imaging (MRI), and gadolinium contrast-enhanced magnetic resonance imaging (cMRI). Includes, (iii) A composition further comprising imaging the biological tissue using fluorescence-based optical imaging (FL).

19. The composition according to claim 18, wherein the method is for imaging cancer tissue.

20. A composition for treating a target cancer using radioisotope therapy, wherein the composition comprises the compound described in Claim 1 or a pharmaceutically acceptable salt thereof, and the compound comprises a radioisotope suitable for radioisotope therapy.

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