US20160287731A1 - Compounds for Positron Emission Tomography - Google Patents

Compounds for Positron Emission Tomography Download PDF

Info

Publication number
US20160287731A1
US20160287731A1 US15/035,936 US201415035936A US2016287731A1 US 20160287731 A1 US20160287731 A1 US 20160287731A1 US 201415035936 A US201415035936 A US 201415035936A US 2016287731 A1 US2016287731 A1 US 2016287731A1
Authority
US
United States
Prior art keywords
conjugate
acid
preceding clauses
formula
methyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US15/035,936
Other languages
English (en)
Inventor
Iontcho R. Vlahov
Christopher P. Leamon
Philip S. Low
Garth L PARHAM
Qingshou CHEN
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Purdue Research Foundation
Endocyte Inc
Original Assignee
Purdue Research Foundation
Endocyte Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Purdue Research Foundation, Endocyte Inc filed Critical Purdue Research Foundation
Priority to US15/035,936 priority Critical patent/US20160287731A1/en
Publication of US20160287731A1 publication Critical patent/US20160287731A1/en
Assigned to PURDUE RESEARCH FOUNDATION reassignment PURDUE RESEARCH FOUNDATION ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: CHEN, Qingshou, LOW, PHILIP S.
Assigned to ENDOCYTE, INC reassignment ENDOCYTE, INC ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: LEAMON, CHRISTOPHER P, PARHAM, GARTH L, VLAHOV, IONTCHO
Abandoned legal-status Critical Current

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/0497—Organic compounds conjugates with a carrier being an organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/041—Heterocyclic compounds
    • A61K51/044—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K51/0459—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with two nitrogen atoms as the only ring hetero atoms, e.g. piperazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/0474—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group
    • A61K51/0482—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group chelates from cyclic ligands, e.g. DOTA
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
    • C07F5/003—Compounds containing elements of Groups 3 or 13 of the Periodic Table without C-Metal linkages
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/52—Use of compounds or compositions for colorimetric, spectrophotometric or fluorometric investigation, e.g. use of reagent paper and including single- and multilayer analytical elements
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/58—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving labelled substances
    • G01N33/60—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving labelled substances involving radioactive labelled substances
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases

Definitions

  • the invention described herein pertains to compounds, compositions, and methods for diagnosing and/or monitoring diseases and disease states using radionuclides.
  • the invention described herein pertains to compounds, compositions, and methods for diagnosing and/or monitoring pathogenic disease states using radionuclides for positron emission tomography (PET).
  • PET positron emission tomography
  • PET is a nuclear imaging methodology that detects pairs of gamma rays emitted indirectly by a positron-producing radionuclide. Because the two emitted gamma rays travel in exactly opposite directions, it is possible to locate their site of origin and thereby reconstruct a three-dimensional image of all positron emitters from a computer analysis of the origins of emitted gamma rays. Compared to other radioimaging modalities, such as SPECT, PET reportedly shows higher sensitivity (about 2 orders of magnitude), better spatial resolution (about 5 mm), greater signal to noise, and superior tracer quantification in both preclinical and clinical applications.
  • PET image acquisition may be routinely performed in about 20 minutes.
  • in vivo PET imaging generally requires only subnanomolar (10 ⁇ 10 to 10 ⁇ 12 ) concentrations of radiotracer, which reportedly minimizes potential damage to other biological systems.
  • PET allows for quantitative dynamic imaging, which may facilitate kinetic studies of target engagement through receptor occupancy. It has been discovered herein that PET agents may be targeted to predetermined tissues using vitamin receptors and/or prostate-specific membrane antigen (PSMA).
  • PSMA prostate-specific membrane antigen
  • vitamin receptors are overexpressed on certain pathogenic cells, including many cancer cell types, activated macrophages, and activated monocytes.
  • folate receptors are overexpressed in many cancers.
  • the folate receptor a 38 KD GPI-anchored protein that binds the vitamin folic acid with high affinity ( ⁇ 1 nM)
  • ⁇ 1 nM a 38 KD GPI-anchored protein that binds the vitamin folic acid with high affinity
  • malignant tissues including ovarian, breast, bronchial, and brain cancers. It is estimated that 95% of all ovarian carcinomas overexpress the folate receptor.
  • normal tissues express low or nondetectable levels of the folate receptor.
  • Most cells also use an unrelated reduced folate carrier to acquire the necessary folic acid.
  • Folate receptors are also overexpressed on activated macrophages, and activated monocytes. Further, it has also been reported that the folate receptor ⁇ , the nonepithelial isoform of the folate receptor, is expressed on activated, but not resting, synovial macrophages. Activated macrophages can participate in the immune response by nonspecifically engulfing and killing foreign pathogens within the macrophage, by displaying degraded peptides from foreign proteins on the macrophage cell surface where they can be recognized by other immune cells, and by secreting cytokines and other factors that modulate the function of T and B lymphocytes, resulting in further stimulation of immune responses. However, activated macrophages can also contribute to the pathophysiology of disease in some instances. For example, activated macrophages can contribute to atherosclerosis, rheumatoid arthritis, autoimmune disease states, and graft versus host disease, among other disease states.
  • vitamin receptors such as folic acid and analogs and derivatives of folic acid to folate receptors
  • rapid endocytosis delivers the vitamin into the cell, where it is unloaded in an endosomal compartment at lower pH.
  • covalent conjugation of small molecules, proteins, and even liposomes to vitamins and other vitamin receptor binding ligands does not block the ability of the ligand to bind to its receptor, and therefore, such ligand conjugates can readily be delivered to and can enter cells by receptor-mediated endocytosis. Accordingly, diagnostic, imaging, and therapeutic agents can be targeted to vitamin receptors, including the folate receptor, for delivery into vitamin receptor expressing cells.
  • the prostate is a male reproductive organ that functions to produce and store seminal fluid, which provides nutrients and fluids for the survival of sperm introduced into the vagina during reproduction. Like other tissues, the prostate gland may develop either malignant (cancerous) or benign (non-cancerous) tumors. Prostate cancer is reportedly one of the most common male cancers in western societies, and is the second leading form of malignancy among American men.
  • PSMA Prostate-specific membrane antigen
  • PSMA is a biomarker that is overexpressed on prostate cancer.
  • PSMA is over-expressed in the malignant prostate tissues when compared to other organs in the human body such as kidney, proximal small intestine, and salivary glands.
  • PSMA is also expressed on the neovasculature within many non-prostate solid tumors, including lung, colon, breast, renal, liver and pancreatic carcinomas, but not on normal vasculature. However, PSMA is expressed minimally in brain.
  • PSMA is a type II cell surface membrane-bound glycoprotein with ⁇ 110 kD molecular weight, including an intracellular segment (amino acids 1-18), a transmembrane domain (amino acids 19-43), and an extensive extracellular domain (amino acids 44-750). Though the functions of the intracellular segment and the transmembrane domains are currently reported to be insignificant, the extracellular domain is involved in several distinct activities. For example, PSMA plays a role in the central nervous system, where it metabolizes N-acetyl-aspartyl glutamate (NAAG) into glutamic and N-acetyl aspartic acid. PSMA also plays a role in the proximal small intestine where it removes ⁇ -linked glutamate from poly- ⁇ -glutamated folate and ⁇ -linked glutamate from peptides and small molecules.
  • NAAG N-acetyl-aspartyl glutamate
  • PSMA is known to undergo rapid internalization into the cell, similar to cell surface bound receptors like vitamin receptors. PSMA is internalized through clathrin-coated pits and subsequently can either recycle to the cell surface or go to lysosomes. Accordingly, diagnostic, imaging, and therapeutic agents can be targeted to PSMA for delivery into PSMA expressing cells, such as prostate cancer cells.
  • the compounds and compositions described herein are useful for targeting and delivering radionuclides for diagnosing and/or monitoring various diseases and disease states caused by pathogenic cell populations.
  • the compounds and compositions described herein are also useful for targeting and delivering radionuclides for treating various diseases and disease states caused by pathogenic cell populations in radiotherapy.
  • compounds and compositions described herein are used for diagnosing and/or monitoring, or treating various diseases and disease states caused by pathogenic cell populations.
  • methods are described herein for administering compounds and compositions described herein for diagnosing and/or monitoring, or treating various diseases and disease states caused by pathogenic cell populations.
  • uses of compounds and compositions are described herein for manufacturing medicaments for diagnosing and/or monitoring, or treating various diseases and disease states caused by pathogenic cell populations.
  • kits are described herein for preparing and/or using compounds and compositions described herein for diagnosing and/or monitoring, or treating various diseases and disease states caused by pathogenic cell populations.
  • FIG. 1A shows a postmortem biodistribution study of 18 F-AIF-QC07017 and 18 F-AIF-QC07043 folate-NOTA-Al— 18 F conjugates in various tissues at 90 minutes post injection in nude mice bearing KB tumor xenografts.
  • the histogram is in groups of 4 from left to right: 18 F-AIF-QC07017, 18 F-AIF-QC07017+excess folic acid, 18 F-AIF-QC07043, 18 F-AIF-QC07043+excess folic acid.
  • FIG. 1B shows a postmortem biodistribution study of 18 F-AIF-QC07017 folate-NOTA-Al— 18 F conjugate in various tissues at 90 minutes post injection in nude mice bearing KB tumor xenografts or A549 tumor xenografts. It is to be understood that the vertical axis has been expanded and that the kidney data is truncated.
  • the histogram is in groups of 4 from left to right: 18 F-AIF-QC07017 against A549 tumor xenografts, 18 F-AIF-QC07017+excess folic acid against A549 tumor xenografts, 18 F-AIF-QC07017 against KB tumor xenografts, 18 F-AIF-QC07017+excess folic acid against KB tumor xenografts.
  • FIG. 1C shows a postmortem biodistribution study of 18 F-AIF-QC07043 folate-NOTA-Al— 18 F conjugate in various tissues at 90 minutes post injection in nude mice bearing KB tumor xenografts or A549 tumor xenografts. It is to be understood that the vertical axis has been expanded and that the kidney data is truncated.
  • the histogram is in groups of 4 from left to right: 18 F-AIF-QC07043 against A549 tumor xenografts, 18 F-AIF-QC07043+excess folic acid against A549 tumor xenografts, 18 F-AIF-QC07043 against KB tumor xenografts, 18 F-AIF-QC07043+excess folic acid against KB tumor xenografts.
  • FIG. 2A shows a postmortem biodistribution study of 18 F-AIF-QC07017 and 18 F-AIF-QC07043 folate-NOTA-Al— 18 F conjugates, compared to 99 mTc-EC20 in KB tumor xenograft tissues at 90 minutes post injection in nude mice.
  • FIG. 2B shows a postmortem biodistribution study of 18 F-AIF-QC07017 and 18 F-AIF-QC07043 folate-NOTA-Al— 18 F conjugates, compared to 99 mTc-EC20 in A549 tumor xenograft tissues at 90 minutes post injection in nude mice.
  • the formulae include and represent not only all pharmaceutically acceptable salts of the compounds, but also include any and all hydrates and/or solvates of the compound formulae. It is appreciated that certain functional groups, such as the hydroxy, amino, and like groups form complexes and/or coordination compounds with water and/or various solvents, in the various physical forms of the compounds. Accordingly, the formulae described herein are to be understood to include and represent those various hydrates and/or solvates. It is also to be understood that the non-hydrates and/or non-solvates of the compound formulae are described by such formula, as well as the hydrates and/or solvates of the compound formulae.
  • composition generally refers to any product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts. It is to be understood that the compositions described herein may be prepared from isolated compounds described herein or from salts, solutions, hydrates, solvates, and other forms of the compounds described herein. It is appreciated that certain functional groups, such as the hydroxy, amino, and like groups form complexes and/or coordination compounds with water and/or various solvents, in the various physical forms of the compounds. It is also to be understood that the compositions may be prepared from various amorphous, non-amorphous, partially crystalline, crystalline, and/or other morphological forms of the compounds described herein.
  • compositions may be prepared from various hydrates and/or solvates of the compounds described herein. Accordingly, such pharmaceutical compositions that recite compounds described herein are to be understood to include each of, or any combination of, the various morphological forms and/or solvate or hydrate forms of the compounds described herein. In addition, it is to be understood that the compositions may be prepared from various co-crystals of the compounds described herein.
  • compositions may include one or more carriers, diluents, and/or excipients.
  • the compounds described herein, or compositions containing them may be formulated in a therapeutically effective amount in any conventional dosage forms appropriate for the methods described herein.
  • the compounds described herein, or compositions containing them, including such formulations may be administered by a wide variety of conventional routes for the methods described herein, and in a wide variety of dosage formats, utilizing known procedures (see generally, Remington: The Science and Practice of Pharmacy, (21 st ed., 2005)).
  • the formulae include and represent each possible isomer, such as stereoisomers and geometric isomers, both individually and in any and all possible mixtures.
  • the formulae include and represent any and all crystalline forms, partially crystalline forms, and non crystalline and/or amorphous forms of the compounds.
  • B is a radical of a targeting agent selected from vitamin receptor binding ligands, PSMA binding ligands, and PSMA inhibitors
  • L is a divalent linker
  • P is a radical of an imaging agent or radiotherapy agent, such as a radionuclide or radionuclide containing group, or a precursor thereof, or a radical of a compound capable of binding a radionuclide or radionuclide containing group, such as a metal chelating group.
  • linker comprises a polypeptide comprising lysine, arginine, or aspartic acid, or a combination thereof.
  • the linker comprises [(CH 2 ) 2 O] n , [(CH 2 ) 2 O] n —(CH 2 ) 2 —C(O), [(CH 2 ) 2 O] n —(CH 2 ) 2 —C(O)NH, [(CH 2 ) 2 O] n —(CH 2 ) 2 —C(O)NH—(CH 2 ) 2 , [(CH 2 ) 2 O] 2 —(CH 2 ) n —C(O)NH—(CH 2 ) 2 NH, where n is an integer from 1 to about 12.
  • the linker comprises (CH 2 ) 2 O—(CH 2 ) 2 —C(O), [(CH 2 ) 2 O] 2 —(CH 2 ) 2 —C(O), [(CH 2 ) 2 O] 6 —(CH 2 ) 2 —C(O), or [(CH 2 )2O] 12 —(CH 2 ) 2 —C(O).
  • the linker comprises (CH 2 ) 2 O—(CH 2 ) 2 —C(O)NH, [(CH 2 ) 2 O] 2 —(CH 2 ) 2 —C(O)NH, [(CH 2 ) 2 O] 6 —(CH 2 ) 2 —C(O)NH, or [(CH 2 ) 2 O] 12 —(CH 2 ) 2 —C(O)NH.
  • the linker comprises (CH 2 ) 2 O—(CH 2 ) 2 —C(O)NH—(CH 2 ) 2 , [(CH 2 ) 2 O] 2 —(CH 2 ) 2 —C(O)NH—(CH 2 ) 2 , [(CH 2 ) 2 O] 6 —(CH 2 ) 2 —C(O)NH—(CH 2 ) 2 , or [(CH 2 ) 2 O] 12 —(CH 2 ) 2 —C(O)NH—(CH 2 ) 2 .
  • the linker comprises (CH 2 ) 2 O—(CH 2 ) 2 —C(O)NH—(CH 2 ) 2 NH, [(CH 2 ) 2 O] 2 —(CH 2 ) 2 —C(O)NH—(CH 2 ) 2 NH, [(CH 2 ) 2 O] 6 —(CH 2 ) 2 —C(O)NH—(CH 2 ) 2 NH, or [(CH 2 ) 2 O] 12 —(CH 2 ) 2 —C(O)NH—(CH 2 ) 2 NH.
  • the linker comprises NH[(CH 2 ) 2 O] n , NH[(CH 2 ) 2 O] n —(CH 2 ) 2 —C(O), NH[(CH 2 ) 2 O] n —(CH 2 ) 2 —C(O)NH, NH[(CH 2 ) 2 O] n —(CH 2 ) 2 —C(O)NH—(CH 2 ) 2 , NH[(CH 2 ) 2 O] n —(CH 2 ) 2 —C(O)NH—(CH 2 ) 2 NH, where n is an integer from 1 to about 12.
  • the linker comprises NH(CH 2 ) 2 O—(CH 2 ) 2 —C(O), NH[(CH 2 ) 2 O] 2 —(CH 2 ) 2 —C(O), NH[(CH 2 ) 2 O] 6 —(CH 2 ) 2 —C(O), or NH[(CH 2 ) 2 O] 12 —(CH 2 ) 2 —C(O).
  • the linker comprises NH(CH 2 ) 2 O—(CH 2 ) 2 —C(O)NH, NH[(CH 2 ) 2 O] 2 —(CH 2 ) 2 —C(O)NH, NH[(CH 2 ) 2 O] 6 —(CH 2 ) 2 —C(O)NH, or NH[(CH 2 ) 2 O] 12 —(CH 2 ) 2 —C(O)NH.
  • the linker comprises NH(CH 2 ) 2 O—(CH 2 ) 2 —C(O)NH—(CH 2 ) 2 , NH[(CH 2 ) 2 O] 2 —(CH 2 ) 2 —C(O)NH—(CH 2 ) 2 , NH[(CH 2 ) 2 O] 6 —(CH 2 ) 2 —C(O)NH—(CH 2 ) 2 , or NH[(CH 2 ) 2 O] 12 —(CH 2 ) 2 —C(O)NH—(CH 2 ) 2 .
  • the linker comprises NH(CH 2 ) 2 O—(CH 2 ) 2 —C(O)NH—(CH 2 ) 2 NH, NH[(CH 2 ) 2 O] 2 —(CH 2 ) 2 —C(O)NH—(CH 2 ) 2 NH, NH[(CH 2 ) 2 O] 6 —(CH 2 ) 2 —C(O)NH—(CH 2 ) 2 NH, or NH[(CH 2 ) 2 O] 12 —(CH 2 ) 2 —C(O)NH—(CH 2 ) 2 NH.
  • the linker comprises NH(CH 2 ) 2 O—(CH 2 ) 2 NH, NH[(CH 2 ) 2 O] 2 —(CH 2 ) 2 NH, NH[(CH 2 ) 2 O] 6 —(CH 2 ) 2 NH, or NH[(CH 2 ) 2 O] 12 —(CH 2 ) 2 NH.
  • linker comprises NH[(CH 2 ) 2 O] n —(CH 2 ) 2 NH—C(O)—(CH 2 ) 2 —C(O), where n is an integer from 1 to about 12.
  • the linker comprises NH(CH 2 ) 2 O—(CH 2 ) 2 NH—C(O)—(CH 2 ) 2 —C(O), NH[(CH 2 ) 2 O] 2 —(CH 2 ) 2 NH—C(O)—(CH 2 ) 2 —C(O), NH[(CH 2 ) 2 O] 6 —(CH 2 ) 2 NH—C(O)—(CH 2 ) 2 —C(O), or NH[(CH 2 ) 2 O] 12 —(CH 2 ) 2 NH—C(O)—(CH 2 ) 2 —C(O).
  • the targeting agent is a radical of a PSMA binding ligand or PSMA inhibitor.
  • n is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; or
  • n is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; or
  • W is O or S.
  • linker comprises a polypeptide comprising phenylalanine, lysine, arginine, or aspartic acid, or a combination thereof.
  • n is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
  • radionuclide is a radiotherapy agent, such as iodine, including 131 I, lutetium, including 177 Lu, yttrium, including 90 Y, strontium, including 89 Sr, samarium, including 153 Sm, and the like, or a radiotherapy agent containing group.
  • a radiotherapy agent such as iodine, including 131 I, lutetium, including 177 Lu, yttrium, including 90 Y, strontium, including 89 Sr, samarium, including 153 Sm, and the like, or a radiotherapy agent containing group.
  • X ⁇ is the conjugate base of an acid, such as trifluoromethanesulfonic acid.
  • X ⁇ is a conjugate base of an acid, such as trifluoromethanesulfonic acid.
  • a pharmaceutical composition comprising one or more of the conjugates of any one of the preceding clauses, in combination with one or more carriers, diluents, or excipients, or a combination thereof.
  • a unit dose or unit dosage form composition comprising a diagnostically effective amount of one or more of the conjugates of any one of the preceding clauses, optionally in combination with one or more carriers, diluents, or excipients, or a combination thereof for diagnosing and/or monitoring a pathogenic cell population, such as a cancer or inflammatory disease.
  • a unit dose or unit dosage form composition comprising a therapeutically effective amount of one or more of the conjugates of any one of the preceding clauses, optionally in combination with one or more carriers, diluents, or excipients, or a combination thereof for treating a pathogenic cell population, such as a cancer or inflammatory disease.
  • a composition for diagnosing and/or monitoring a disease or disease state caused at least in part by a pathogenic cell population, such as a cancer or inflammatory disease, in a host animal comprising a diagnostically effective amount of one or more of the conjugates of any one of the preceding clauses; or a pharmaceutical composition comprising a diagnostically effective amount of one or more of the conjugates of any one of the preceding clauses, optionally further comprising one or more carriers, diluents, or excipients, or a combination thereof.
  • a composition for treating a disease or disease state caused at least in part by a pathogenic cell population, such as a cancer or inflammatory disease, in a host animal comprising a therapeutically effective amount of one or more of the conjugates of any one of the preceding clauses; or a pharmaceutical composition comprising a therapeutically effective amount of one or more of the conjugates of any one of the preceding clauses, optionally further comprising one or more carriers, diluents, or excipients, or a combination thereof.
  • a method for diagnosing and/or monitoring a disease or disease state caused at least in part by a pathogenic cell population, such as a cancer or inflammatory disease, in a host animal comprising the step of administering to the host animal a diagnostically effective amount of one or more of the conjugates of any one of the preceding clauses; or a pharmaceutical composition comprising a diagnostically effective amount of one or more of the conjugates of any one of the preceding clauses, optionally further comprising one or more carriers, diluents, or excipients, or a combination thereof.
  • a method for treating a disease or disease state caused at least in part by a pathogenic cell population, such as a cancer or inflammatory disease, in a host animal comprising the step of administering to the host animal a therapeutically effective amount of one or more of the conjugates of any one of the preceding clauses; or a pharmaceutical composition comprising a therapeutically effective amount of one or more of the conjugates of any one of the preceding clauses, optionally further comprising one or more carriers, diluents, or excipients, or a combination thereof.
  • a kit comprising one or more of the conjugates of any one of the preceding clauses, or a pharmaceutical composition thereof, optionally further comprising one or more carriers, diluents, or excipients, or a combination thereof; an optional solvent; an optional reaction container, and a set of instructions for preparing one or more radionuclides and combining the one or more radionuclides with the one or more of the conjugates to prepare an imaging agent, diagnostic agent, or therapeutic agent.
  • a kit comprising one or more of the conjugates of any one of the preceding clauses, or a pharmaceutical composition thereof, optionally further comprising one or more carriers, diluents, or excipients, or a combination thereof; an optional solvent; an optional reaction container, and a set of instructions for preparing one or more radionuclides and combining the one or more radionuclides with the one or more of the conjugates to prepare an imaging agent, diagnostic agent, or therapeutic agent.
  • the conjugate, composition, unit dose, method, use, or kit of any other embodiment described herein comprises a compound of formula
  • each R is in each instance independently selected to form a carboxylic acid or salt thereof, ester, or amide, and R 1 , R 2 , and R 3 , are each independently selected from hydrogen, and alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl, each of which is optionally substituted.
  • the conjugate, composition, unit dose, method, use, or kit of any other embodiment described herein comprises 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) or a derivative thereof comprising a chelated metal; or a radical of the foregoing.
  • DOTA 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid
  • a derivative thereof comprising a chelated metal
  • the conjugate, composition, unit dose, method, use, or kit of any other embodiment described herein comprises a compound of formula
  • each R is in each instance independently selected to form a carboxylic acid or salt thereof, ester, or amide
  • R 1 , R 2 , and R 3 are each independently selected from hydrogen, and alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl, each of which is optionally substituted, such as the following illustrative compounds:
  • the conjugate, composition, unit dose, method, use, or kit of any other embodiment described herein comprises a compound of formula
  • R 4 and R 5 are selected from hydrogen, and alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl, each of which is optionally substituted, such as the following illustrative compounds:
  • R 4 R 5 or a carboxylic acid salt or carboxamide derivative (CONH 2 ) thereof, or a radical of any of the foregoing; or a derivative thereof comprising a chelated metal.
  • the conjugate, composition, unit dose, method, use, or kit of any other embodiment described herein comprises a compound of formula
  • the conjugate, composition, unit dose, method, use, or kit of any other embodiment described herein comprises a compound selected from the formulae
  • n is an integer selected from 1, 2, 3, 4, 5, or 6; or a derivative thereof comprising a chelated metal.
  • radical generally refers to an open valence compound or chemical fragment that results after the removal of a hydrogen atom or a hydroxyl group from a carboxylic acid.
  • radicals may be formed from L-NETA
  • each (*) atom is an open valence for attachment to a linker and/or targeting agent.
  • n 0 or 1
  • NX is
  • n 1 or 3.
  • the compounds described herein may contain one or more chiral centers, or may otherwise be capable of existing as multiple stereoisomers. It is to be understood that in one embodiment, the invention described herein is not limited to any particular sterochemical requirement, and that the compounds, and compositions, methods, uses, and medicaments that include them may be optically pure, or may be any of a variety of stereoisomeric mixtures, including racemic and other mixtures of enantiomers, other mixtures of diastereomers, and the like. It is also to be understood that such mixtures of stereoisomers may include a single stereochemical configuration at one or more chiral centers, while including mixtures of stereochemical configuration at one or more other chiral centers.
  • the compounds described herein may include geometric centers, such as cis, trans, E, and Z double bonds. It is to be understood that in another embodiment, the invention described herein is not limited to any particular geometric isomer requirement, and that the compounds, and compositions, methods, uses, and medicaments that include them may be pure, or may be any of a variety of geometric isomer mixtures. It is also to be understood that such mixtures of geometric isomers may include a single configuration at one or more double bonds, while including mixtures of geometry at one or more other double bonds.
  • alkyl includes a chain of carbon atoms, which is optionally branched.
  • alkenyl and alkynyl each include a chain of carbon atoms, which is optionally branched, and include at least one double bond or triple bond, respectively. It is to be understood that alkynyl may also include one or more double bonds. It is to be further understood that in certain embodiments, alkyl is advantageously of limited length, including C 1 -C 24 , C 1 -C 12 , C 1 -C 8 , C 1 -C 6 , and C 1 -C 4 .
  • alkenyl and/or alkynyl may each be advantageously of limited length, including C 2 -C 24 , C 2 -C 12 , C 2 -C 8 , C 2 -C 6 , and C 2 -C 4 .
  • alkenyl and/or alkynyl groups including C 2 -C 8 , C 2 -C 6 , and C 2 -C 4 may be referred to as lower alkenyl and/or alkynyl.
  • alkyl refers to alkyl as defined herein, and optionally lower alkyl.
  • alkenyl refers to alkenyl as defined herein, and optionally lower alkenyl.
  • alkynyl refers to alkynyl as defined herein, and optionally lower alkynyl.
  • Illustrative alkyl, alkenyl, and alkynyl groups are, but not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, 3-pentyl, neopentyl, hexyl, heptyl, octyl, and the like, and the corresponding groups containing one or more double and/or triple bonds, or a combination thereof.
  • alkylene includes a divalent chain of carbon atoms, which is optionally branched.
  • alkenylene and alkynylene includes a divalent chain of carbon atoms, which is optionally branched, and includes at least one double bond or triple bond, respectively. It is to be understood that alkynylene may also include one or more double bonds. It is to be further understood that in certain embodiments, alkylene is advantageously of limited length, including C 1 -C 24 , C 1 -C 12 , C 1 -C 8 , C 1 -C 6 , and C 1 -C 4 .
  • alkenylene and/or alkynylene may each be advantageously of limited length, including C 2 -C 24 , C 2 -C 12 , C 2 -C 8 , C 2 -C 6 , and C 2 -C 4 .
  • alkenylene and/or alkynylene groups including C 2 -C 8 , C 2 -C 6 , and C 2 -C 4 may be referred to as lower alkenylene and/or alkynylene.
  • alkylene, alkenylene, and/or alkynylene groups may add less lipophilicity to the compound and accordingly will have different pharmacokinetic behavior.
  • alkylene, alkenylene, and alkynylene refers to alkylene, alkenylene, and alkynylene as defined herein, and optionally lower alkylene, alkenylene, and alkynylene.
  • Illustrative alkyl groups are, but not limited to, methylene, ethylene, n-propylene, isopropylene, n-butylene, isobutylene, sec-butylene, pentylene, 1,2-pentylene, 1,3-pentylene, hexylene, heptylene, octylene, and the like.
  • linker includes is a chain of atoms that connects two or more functional parts of a molecule to form a conjugate.
  • the chain of atoms is selected from C, N, O, S, Si, and P, or C, N, O, S, and P, or C, N, O, and S.
  • the chain of atoms covalently connects different functional capabilities of the conjugate, such as targeting agents, drugs, diagnostic agents, imaging agents, and the like.
  • the linker may have a wide variety of lengths, such as in the range from about 2 to about 100 atoms in the contiguous backbone.
  • the atoms used in forming the linker may be combined in all chemically relevant ways, such as chains of carbon atoms forming alkylene, alkenylene, and alkynylene groups, and the like; chains of carbon and oxygen atoms forming ethers, polyoxyalkylene groups, or when combined with carbonyl groups forming esters and carbonates, and the like; chains of carbon and nitrogen atoms forming amines, imines, polyamines, hydrazines, hydrazones, or when combined with carbonyl groups forming amides, ureas, semicarbazides, carbazides, and the like; chains of carbon, nitrogen, and oxygen atoms forming alkoxyamines, alkoxylamines, or when combined with carbonyl groups forming urethanes, amino acids, acyloxylamines, hydroxamic acids, and the like; and many others.
  • the atoms forming the chain in each of the foregoing illustrative embodiments may be either saturated or unsaturated, thus forming single, double, or triple bonds, such that for example, alkanes, alkenes, alkynes, imines, and the like may be radicals that are included in the linker.
  • the atoms forming the linker may also be cyclized upon each other or be part of cyclic structure to form divalent cyclic structures that form the linker, including cyclo alkanes, cyclic ethers, cyclic amines, and other heterocycles, arylenes, heteroarylenes, and the like in the linker.
  • the linker length may be defined by any pathway through the one or more cyclic structures.
  • the linker length is defined by the shortest pathway through the each one of the cyclic structures.
  • the linkers may be optionally substituted at any one or more of the open valences along the chain of atoms, such as optional substituents on any of the carbon, nitrogen, silicon, or phosphorus atoms.
  • the linker may connect the two or more functional parts of a molecule to form a conjugate at any open valence, and it is not necessary that any of the two or more functional parts of a molecule forming the conjugate are attached at any apparent end of the linker.
  • cycloalkyl includes a chain of carbon atoms, which is optionally branched, where at least a portion of the chain in cyclic. It is to be understood that cycloalkylalkyl is a subset of cycloalkyl. It is to be understood that cycloalkyl may be polycyclic. Illustrative cycloalkyl include, but are not limited to, cyclopropyl, cyclopentyl, cyclohexyl, 2-methylcyclopropyl, cyclopentyleth-2-yl, adamantyl, and the like.
  • cycloalkenyl includes a chain of carbon atoms, which is optionally branched, and includes at least one double bond, where at least a portion of the chain in cyclic. It is to be understood that the one or more double bonds may be in the cyclic portion of cycloalkenyl and/or the non-cyclic portion of cycloalkenyl. It is to be understood that cycloalkenylalkyl and cycloalkylalkenyl are each subsets of cycloalkenyl. It is to be understood that cycloalkyl may be polycyclic.
  • Illustrative cycloalkenyl include, but are not limited to, cyclopentenyl, cyclohexylethen-2-yl, cycloheptenylpropenyl, and the like. It is to be further understood that chain forming cycloalkyl and/or cycloalkenyl is advantageously of limited length, including C 3 -C 24 , C 3 -C 12 , C 3 -C 8 , C 3 -C 6 , and C 5 -C 6 . It is appreciated herein that shorter alkyl and/or alkenyl chains forming cycloalkyl and/or cycloalkenyl, respectively, may add less lipophilicity to the compound and accordingly will have different pharmacokinetic behavior.
  • heteroalkyl includes a chain of atoms that includes both carbon and at least one heteroatom, and is optionally branched.
  • Illustrative heteroatoms include nitrogen, oxygen, and sulfur. In certain variations, illustrative heteroatoms also include phosphorus, and selenium.
  • cycloheteroalkyl including heterocyclyl and heterocycle, includes a chain of atoms that includes both carbon and at least one heteroatom, such as heteroalkyl, and is optionally branched, where at least a portion of the chain is cyclic.
  • Illustrative heteroatoms include nitrogen, oxygen, and sulfur. In certain variations, illustrative heteroatoms also include phosphorus, and selenium.
  • Illustrative cycloheteroalkyl include, but are not limited to, tetrahydrofuryl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, morpholinyl, piperazinyl, homopiperazinyl, quinuclidinyl, and the like.
  • aryl includes monocyclic and polycyclic aromatic carbocyclic groups, each of which may be optionally substituted.
  • Illustrative aromatic carbocyclic groups described herein include, but are not limited to, phenyl, naphthyl, and the like.
  • heteroaryl includes aromatic heterocyclic groups, each of which may be optionally substituted.
  • Illustrative aromatic heterocyclic groups include, but are not limited to, pyridinyl, pyrimidinyl, pyrazinyl, triazinyl, tetrazinyl, quinolinyl, quinazolinyl, quinoxalinyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, benzimidazolyl, benzoxazolyl, benzthiazolyl, benzisoxazolyl, benzisothiazolyl, and the like.
  • optionally substituted includes the replacement of hydrogen atoms with other functional groups on the radical that is optionally substituted.
  • Such other functional groups illustratively include, but are not limited to, amino, hydroxyl, halo, thiol, alkyl, haloalkyl, heteroalkyl, aryl, arylalkyl, arylheteroalkyl, heteroaryl, heteroarylalkyl, heteroarylheteroalkyl, nitro, sulfonic acids and derivatives thereof, carboxylic acids and derivatives thereof, and the like.
  • any of amino, hydroxyl, thiol, alkyl, haloalkyl, heteroalkyl, aryl, arylalkyl, arylheteroalkyl, heteroaryl, heteroarylalkyl, heteroarylheteroalkyl, and/or sulfonic acid is optionally substituted.
  • aryl subsituents include, but are not limited to, amino, hydroxy, halo, thio, alkyl, haloalkyl, heteroalkyl, aryl, arylalkyl, arylheteroalkyl, heteroaryl, heteroarylalkyl, heteroarylheteroalkyl, nitro, sulfonic acids and derivatives thereof, carboxylic acids and derivatives thereof, and the like.
  • any of amino, hydroxy, thio, alkyl, haloalkyl, heteroalkyl, aryl, arylalkyl, arylheteroalkyl, heteroaryl, heteroarylalkyl, heteroarylheteroalkyl, and/or sulfonic acid is optionally substituted.
  • Illustrative substituents include, but are not limited to, a radical —(CH 2 ) x Z X , where x is an integer from 0-6 and Z X is selected from halogen, hydroxy, alkanoyloxy, including C 1 -C 6 alkanoyloxy, optionally substituted aroyloxy, alkyl, including C 1 -C 6 alkyl, alkoxy, including C 1 -C 6 alkoxy, cycloalkyl, including C 3 -C 8 cycloalkyl, cycloalkoxy, including C 3 -C 8 cycloalkoxy, alkenyl, including C 2 -C 6 alkenyl, alkynyl, including C 2 -C 6 alkynyl, haloalkyl, including C 1 -C 6 haloalkyl, haloalkoxy, including C 1 -C 6 haloalkoxy, halocycloalkyl, including C 3 -C 8
  • n is an integer from 0 to 8
  • the individual and selectable values of 0, 1, 2, 3, 4, 5, 6, 7, and 8 such as n is 0, or n is 1, or n is 2, etc.
  • the recitation that n is an integer from 0 to 8 also describes each and every subrange, each of which may for the basis of a further embodiment, such as n is an integer from 1 to 8, from 1 to 7, from 1 to 6, from 2 to 8, from 2 to 7, from 1 to 3, from 2 to 4, etc.
  • composition generally refers to any product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts. It is to be understood that the compositions described herein may be prepared from isolated compounds described herein or from salts, solutions, hydrates, solvates, and other forms of the compounds described herein. It is appreciated that certain functional groups, such as the hydroxy, amino, and like groups form complexes and/or coordination compounds with water and/or various solvents, in the various physical forms of the compounds. It is also to be understood that the compositions may be prepared from various amorphous, non-amorphous, partially crystalline, crystalline, and/or other morphological forms of the compounds described herein.
  • compositions may be prepared from various hydrates and/or solvates of the compounds described herein. Accordingly, such pharmaceutical compositions that recite compounds described herein are to be understood to include each of, or any combination of, the various morphological forms and/or solvate or hydrate forms of the compounds described herein.
  • compositions may include one or more carriers, diluents, and/or excipients.
  • the compounds described herein, or compositions containing them may be formulated in a diagnostically or therapeutically effective amount in any conventional dosage forms appropriate for the methods described herein.
  • the compounds described herein, or compositions containing them, including such formulations may be administered by a wide variety of conventional routes for the methods described herein, and in a wide variety of dosage formats, utilizing known procedures (see generally, Remington: The Science and Practice of Pharmacy, (21 st ed., 2005)).
  • diagnostically effective amount refers to that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes diagnosis and/or monitoring of the symptoms of the disease or disorder being treated.
  • Illustrative diagnostically effective amounts of the conjugate to be administered to the host animal include about 1 pg/kg to about 10 mg/kg, 1 ng/kg to about 10 mg/kg, or from about 10 ⁇ g/kg to about 1 mg/kg, or from about 100 ⁇ g/kg to about 500 ⁇ g/kg.
  • therapeutically effective amount refers to that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease or disorder being treated.
  • the therapeutically effective amount is that which may treat or alleviate the disease or symptoms of the disease at a reasonable benefit/risk ratio applicable to any medical treatment.
  • the total daily usage of the compounds and compositions described herein may be decided by the attending physician within the scope of sound medical judgment.
  • the specific therapeutically-effective dose level for any particular patient will depend upon a variety of factors, including the disorder being treated and the severity of the disorder; activity of the specific compound employed; the specific composition employed; the age, body weight, general health, gender and diet of the patient: the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidentally with the specific compound employed; and like factors well known to the researcher, veterinarian, medical doctor or other clinician of ordinary skill.
  • Illustrative therapeutically effective amounts of the conjugate to be administered to the host animal include about 1 pg/kg to about 10 mg/kg, 1 ng/kg to about 10 mg/kg, or from about 10 ⁇ g/kg to about 1 mg/kg, or from about 100 ⁇ g/kg to about 500 ⁇ g/kg.
  • administering includes all means of introducing the compounds and compositions described herein to the host animal, including, but are not limited to, oral (po), intravenous (iv), intramuscular (im), subcutaneous (sc), transdermal, inhalation, buccal, ocular, sublingual, vaginal, rectal, and the like.
  • the compounds and compositions described herein may be administered in unit dosage forms and/or formulations containing conventional nontoxic pharmaceutically-acceptable carriers, adjuvants, and/or vehicles.
  • amino acid refers generally to beta, gamma, and longer amino acids, such as amino acids of the formula:
  • R is hydrogen, alkyl, acyl, or a suitable nitrogen protecting group
  • R′ and R′′ are hydrogen or a substituent, each of which is independently selected in each occurrence, and q is an integer such as 1, 2, 3, 4, or 5.
  • R′ and/or R′′ independently correspond to, but are not limited to, hydrogen or the side chains present on naturally occurring amino acids, such as methyl, benzyl, hydroxymethyl, thiomethyl, carboxyl, carboxylmethyl, guanidinopropyl, and the like, and derivatives and protected derivatives thereof.
  • the above described formula includes all stereoisomeric variations.
  • the amino acid may be selected from alanine, aspartic acid, asparagine, cysteine, glutamic acid, phenylalanine, histidine, isoleucine, lysine, leucine, methionine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, tyrosine, and ornithine, and the like.
  • n is an integer from 0 to 8
  • the individual and selectable values of 0, 1, 2, 3, 4, 5, 6, 7, and 8 such as n is 0, or n is 1, or n is 2, etc.
  • the recitation that n is an integer from 0 to 8 also describes each and every subrange, each of which may for the basis of a further embodiment, such as n is an integer from 1 to 8, from 1 to 7, from 1 to 6, from 2 to 8, from 2 to 7, from 1 to 3, from 2 to 4, etc.
  • linkers described herein include a polyether, such as the linkers of the following formulae:
  • m is an integer independently selected in each instance from 1 to about 8; p is an integer selected from 1 to about 10; and n is an integer independently selected in each instance from 1 to about 3.
  • m is independently in each instance 1 to about 3.
  • n is 1 in each instance.
  • p is independently in each instance about 4 to about 6.
  • the corresponding polypropylene polyethers corresponding to the foregoing are described herein and may be included in the conjugates as linkers.
  • mixed polyethylene and polypropylene polyethers may be included in the conjugates as linkers.
  • cyclic variations of the foregoing polyether compounds such as those that include tetrahydrofuranyl, 1,3-dioxanes, 1,4-dioxanes, and the like are described herein.
  • the linkers described herein include a plurality of hydroxyl functional groups, such as linkers that incorporate monosaccharides, oligosaccharides, polysaccharides, and the like. It is to be understood that the polyhydroxyl containing linkers comprise a plurality of —(CROH)— groups, where R is hydrogen or alkyl.
  • the linkers include one or more of the following diradicals:
  • R is H, alkyl, cycloalkyl, or arylalkyl; m is an integer from 1 to about 3; n1 is an integer from 1 to about 5, or n1 is an integer from 2 to about 5, p is an integer from 1 to about 5, and r is an integer selected from 1 to about 3.
  • the integer n is 3 or 4.
  • the integer p is 3 or 4.
  • the integer r is 1.
  • the linkers include one or more of the following diradicals:
  • R is H, alkyl, cycloalkyl, or arylalkyl; m is an integer from 1 to about 3; n is an integer from 1 to about 5, or from 2 to about 5, p is an integer from 1 to about 5, and r is an integer selected from 1 to about 3. In one aspect, the integer n is 3 or 4. In another aspect, the integer p is 3 or 4. In another aspect, the integer r is 1.
  • the linker includes one or more of the following cyclic polyhydroxyl groups:
  • n is an integer from 2 to about 5
  • p is an integer from 1 to about 5
  • each r is an independently selected integer from 1 to about 4.
  • the integer n is 3 or 4.
  • the integer p is 3 or 4.
  • each integer r is independently 2 or 3.
  • n is equal to or less than r, such as when r is 2 or 3, n is 1 or 2, or 1, 2, or 3, respectively.
  • the linker includes a polyhydroxyl compound of the following formula:
  • the linker includes one or more polyhydroxyl compounds of the following formulae:
  • the section may be derived from ribose, xylose, glucose, mannose, galactose, or other sugar and retain the stereochemical arrangements of pendant hydroxyl and alkyl groups present on those molecules.
  • the linkers L described herein include polyhydroxyl groups that are spaced away from the backbone of the linker.
  • such carbohydrate groups or polyhydroxyl groups are connected to the back bone by a triazole group, forming triazole-linked linkers.
  • such linkers include diradicals of the following formulae:
  • n, m, and r are integers and are each independently selected in each instance from 1 to about 5.
  • m is independently 2 or 3 in each instance.
  • r is 1 in each instance.
  • n is 1 in each instance.
  • the group connecting the polyhydroxyl group to the backbone of the linker is a different heteroaryl group, including but not limited to, pyrrole, pyrazole, 1,2,4-triazole, furan, oxazole, isoxazole, thienyl, thiazole, isothiazole, oxadiazole, and the like.
  • divalent 6-membered ring heteroaryl groups are described.
  • Other variations of the foregoing illustrative linkers include oxyalkylene groups, such as the following formulae:
  • n and r are integers and are each independently selected in each instance from 1 to about 5; and p is an integer selected from 1 to about 4.
  • such carbohydrate groups or polyhydroxyl groups are connected to the back bone by an amide group, forming amide-linked linkers.
  • linkers include diradicals of the following formulae:
  • each n is an independently selected integer from 1 to about 3, and m is an independently selected integer from 1 to about 22.
  • each n is independently 1 or 2.
  • m is selected from about 6 to about 10, illustratively 8.
  • the group connecting the polyhydroxyl group to the backbone of the linker is a different functional group, including but not limited to, esters, ureas, carbamates, acylhydrazones, and the like.
  • cyclic variations are described.
  • Other variations of the foregoing illustrative linkers include oxyalkylene groups, such as the following formulae:
  • n is in each instance an independently selected integer from 1 to about 5; and p is an integer selected from 1 to about 4.
  • the linkers include one or more of the following diradicals:
  • R is H, alkyl, cycloalkyl, or arylalkyl; each m is an independently selected integer from 1 to about 3; each n is an independently selected integer from 1 to about 6, p is an integer from 1 to about 5, and r is an integer selected from 1 to about 3. In one variation, each n is independently 3 or 4. In another variation, the integer p is 3 or 4. In another variation, the integer r is 1.
  • the linkers include one or more of the following diradicals:
  • R is H, alkyl, cycloalkyl, or arylalkyl; each m is an independently selected integer from 1 to about 3; each n is an independently selected integer from 2 to about 6, p is an integer from 1 to about 5, and r is an integer selected from 1 to about 3. In one variation, each n is independently 3 or 4. In another variation, the integer p is 3 or 4. In another variation, the integer r is 1.
  • the linkers include one or more of the following diradicals:
  • each n is independently 3 or 4.
  • the integer p is 3 or 4.
  • the integer r is 1.
  • the linkers include one or more of the following diradicals:
  • each n is independently 3 or 4.
  • the integer p is 3 or 4.
  • the integer r is 1.
  • the linkers include one or more of the following diradicals:
  • each m is an independently selected integer from 1 to about 3
  • p is an integer from 1 to about 5
  • r is an integer selected from 1 to about 3.
  • the integer p is 3 or 4.
  • the integer r is 1.
  • the linker is a combination of backbone and branching side motifs such as is illustrated by the following formulae
  • n is an integer independently selected in each instance from 0 to about 3.
  • the above formula are intended to represent 4, 5, 6, and even larger membered cyclic sugars.
  • the above formula may be modified to represent deoxy sugars, where one or more of the hydroxy groups present on the formulae are replaced by hydrogen, alkyl, or amino.
  • the corresponding carbonyl compounds are described by the above formulae, where one or more of the hydroxyl groups is oxidized to the corresponding carbonyl.
  • the pyranose includes both carboxyl and amino functional groups and (a) can be inserted into the backbone and (b) can provide synthetic handles for branching side chains in variations of this embodiment.
  • any of the pendant hydroxyl groups may be used to attach other chemical radicals, including additional sugars to prepare the corresponding oligosaccharides.
  • Other variations of this embodiment are also described, including inserting the pyranose or other sugar into the backbone at a single carbon, i.e. a spiro arrangement, at a geminal pair of carbons, and like arrangements.
  • one or two ends of the linker, or the agent P, or the ligand B may be connected to the sugar to be inserted into the backbone in a 1,1; 1,2; 1,3; 1,4; 2,3, or other arrangement.
  • the linkers include one or more amino groups of the following formulae:
  • each n is an integer independently selected in each instance from 1 to about 3. In one aspect, the each n is independently 1 or 2 in each instance. In another aspect, the integer n is 1 in each instance.
  • the linker is a sulfuric acid ester, such as an alkyl ester of sulfuric acid.
  • the linker is of the following formula:
  • each n is an integer independently selected in each instance from 1 to about 3.
  • each n is independently 1 or 2 in each instance.
  • n is an independently selected integer from 2 to about 5
  • p is an integer from 1 to about 5
  • r is an integer from 1 to about 4, as described above.
  • open positions such as (*) atoms are locations for attachment of the targeting agent B or the agent (P).
  • attachment of either or both of B and A may be direct or through an intervening linker.
  • Illustrative additional linkers are described in U.S. Pat. No. 7,601,332, the disclosure of which is incorporated herein by reference.
  • bivalent linkers may be combined in any chemically relevant way, either directly or via an intervening heteroatom to construct the linkers described herein.
  • the polyvalent linkers described herein comprise a linker selected from the group consisting of carbonyl, thionocarbonyl, alkylene, cycloalkylene, alkylenecycloalkyl, alkylenecarbonyl, cycloalkylenecarbonyl, carbonylalkylcarbonyl, 1 alkylenesuccinimid-3-yl, 1 (carbonylalkyl)succinimid-3-yl, alkylenesulfoxyl, sulfonylalkyl, alkylenesulfoxylalkyl, alkylenesulfonylalkyl, carbonyltetrahydro-2H-pyranyl, carbonyltetrahydrofuranyl, 1-(carbonyltetrahydro-2H-pyranyl)succinimid-3-yl, and 1-(carbonyltetrahydrofuranyl)succinimid-3-yl.
  • the compounds described herein comprise one or more amino acids.
  • the compounds described herein can be used for both human clinical medicine and veterinary applications.
  • the host animal harboring the population of pathogenic cells and administered the compounds described herein can be human or, in the case of veterinary applications, can be a laboratory, agricultural, domestic, or wild animal.
  • the present invention can be applied to host animals including, but not limited to, humans, laboratory animals such rodents (e.g., mice, rats, hamsters, etc.), rabbits, monkeys, chimpanzees, domestic animals such as dogs, cats, and rabbits, agricultural animals such as cows, horses, pigs, sheep, goats, and wild animals in captivity such as bears, pandas, lions, tigers, leopards, elephants, zebras, giraffes, gorillas, dolphins, and whales.
  • rodents e.g., mice, rats, hamsters, etc.
  • rabbits, monkeys, chimpanzees domestic animals
  • domestic animals such as dogs, cats
  • rabbits agricultural animals
  • cows, horses, pigs, sheep, goats and wild animals in captivity
  • pathogenic cells or “population of pathogenic cells” generally refers to cancer cells, infectious agents such as bacteria and viruses, bacteria- or virus-infected cells, inflammatory cells, activated macrophages capable of causing a disease state, and any other type of pathogenic cells that uniquely express, preferentially express, or overexpress binding sites for the targeting agents described herein.
  • the population of pathogenic cells can be a cancer cell population that is tumorigenic, including benign tumors and malignant tumors, or it can be non-tumorigenic.
  • the cancer cell population can arise spontaneously or by such processes as mutations present in the germline of the host animal or somatic mutations, or it can be chemically-, virally-, or radiation-induced.
  • the invention can be utilized to diagnose, monitor, and/or treat such cancers, including carcinomas, sarcomas, lymphomas, Hodgekin's disease, melanomas, mesotheliomas, Burkitt's lymphoma, nasopharyngeal carcinomas, leukemias, and myelomas.
  • the cancer cell population can include, but is not limited to, oral, thyroid, endocrine, skin, gastric, esophageal, laryngeal, pancreatic, colon, bladder, bone, ovarian, cervical, uterine, breast, testicular, prostate, rectal, kidney, liver, and lung cancers.
  • the population of pathogenic cells can also be activated monocytes or macrophages associated with disease states such as fibromyalgia, rheumatoid arthritis, osteoarthritis, ulcerative colitis, Crohn's disease, psoriasis, osteomyelitis, multiple sclerosis, atherosclerosis, pulmonary fibrosis, sarcoidosis, systemic sclerosis, organ transplant rejection (GVHD), lupus erythematosus, Sjogren's syndrome, glomerulonephritis, inflammations of the skin, such as psoriasis, and the like, chronic inflammations, and inflammations due to injury, such as head or spinal cord injury, embolisms, and the like.
  • disease states such as fibromyalgia, rheumatoid arthritis, osteoarthritis, ulcerative colitis, Crohn's disease, psoriasis, osteomyelitis, multiple sclerosis, atherosclerosis, pulmonary fibrosis
  • the conjugates described herein can be formed from, for example, a wide variety of vitamins or receptor-binding vitamin analogs/derivatives, linkers, and imaging and radiotherapy agents.
  • the conjugates described herein are capable of selectively targeting a population of pathogenic cells in the host animal due to preferential expression of a receptor for the targeting agent, such as a vitamin, accessible for binding, on the pathogenic cells.
  • Illustrative vitamin moieties that can be used as the targeting agent (B) include carnitine, inositol, lipoic acid, pyridoxal, ascorbic acid, niacin, pantothenic acid, folic acid, riboflavin, thiamine, biotin, vitamin B 12 , and the lipid soluble vitamins A, D, E and K. These vitamins, and their receptor-binding analogs and derivatives, constitute an illustrative targeting entity that can be coupled with the imaging or radiotherapy agent by a bivalent linker (L) to form a targeting agent (B) imaging or radiotherapy agent conjugate as described herein.
  • the term vitamin is understood to include vitamin analogs and/or derivatives, unless otherwise indicated.
  • biotin analogs such as biocytin, biotin sulfoxide, oxybiotin and other biotin receptor-binding compounds, and the like, are considered to be vitamins, vitamin analogs, and vitamin derivatives.
  • vitamin analogs or derivatives as described herein refer to vitamins that incorporates an heteroatom through which the vitamin analog or derivative is covalently bound to the bivalent linker (L).
  • Illustrative vitamin moieties include folic acid, biotin, riboflavin, thiamine, vitamin B 12 , and receptor-binding analogs and derivatives of these vitamin molecules, and other related vitamin receptor binding molecules.
  • the targeting group B is a folate, an analog of folate, or a derivative of folate. It is to be understood as used herein, that the term folate is used both individually and collectively to refer to folic acid itself, and/or to such analogs and derivatives of folic acid that are capable of binding to folate receptors.
  • vitamin analogs and/or derivatives include folate and analogs and derivatives of folate such as folinic acid, pteropolyglutamic acid, and folate receptor-binding pteridines such as tetrahydropterins, dihydrofolates, tetrahydrofolates, and their deaza and dideaza analogs.
  • folate and analogs and derivatives of folate such as folinic acid, pteropolyglutamic acid, and folate receptor-binding pteridines such as tetrahydropterins, dihydrofolates, tetrahydrofolates, and their deaza and dideaza analogs.
  • deaza and “dideaza” analogs refer to the art-recognized analogs having a carbon atom substituted for one or two nitrogen atoms in the naturally occurring folic acid structure, or analog or derivative thereof.
  • the deaza analogs include the 1-deaza, 3-deaza, 5-deaza, 8-deaza, and 10-deaza analogs of folate, folinic acid, pteropolyglutamic acid, and folate receptor-binding pteridines such as tetrahydropterins, dihydrofolates, and tetrahydrofolates.
  • the dideaza analogs include, for example, 1,5-dideaza, 5,10-dideaza, 8,10-dideaza, and 5,8-dideaza analogs of folate, folinic acid, pteropolyglutamic acid, and folate receptor-binding pteridines such as tetrahydropterins, dihydrofolates, and tetrahydrofolates.
  • folates useful as complex forming ligands for this invention are the folate receptor-binding analogs aminopterin, amethopterin (also known as methotrexate), N 10 -methylfolate, 2-deamino-hydroxyfolate, deaza analogs such as 1-deazamethopterin or 3-deazamethopterin, and 3′,5′-dichloro-4-amino-4-deoxy-N 10 -methylpteroylglutamic acid (dichloromethotrexate).
  • folic acid analogs and/or derivatives are conventionally termed “folates,” reflecting their ability to bind with folate-receptors, and such ligands when conjugated with exogenous molecules are effective to enhance transmembrane transport, such as via folate-mediated endocytosis as described herein.
  • X and Y are each-independently selected from the group consisting of halo, R 2 , OR 2 , SR 3 , and NR 4 R 5 ;
  • U, V, and W represent divalent moieties each independently selected from the group consisting of (R 6a )C ⁇ , N ⁇ , (R 6a )C(R 7a ), and N(R 4a );
  • Q is selected from the group consisting of C and CH;
  • T is selected from the group consisting of S, O, N, NH, and —C ⁇ C—;
  • a 1 and A 2 are each independently selected from the group consisting of oxygen, sulfur, C(Z), C(Z)O, OC(Z), N(R 4b ), C(Z)N(R 4b ), N(R 4b )C(Z), OC(Z)N(R 4b ), N(R 4b )C(Z)O, N(R 4b )C(Z)N(R 5b ), S(O), S(O) 2 , N(R 4a )S(O) 2 , C(R 6b )(R 7b ), N(C ⁇ H), N(CH 2 ⁇ CH), C 1 -C 12 alkylene, and C 1 -C 12 alkyeneoxy, where Z is oxygen or sulfur;
  • R 1 is selected-from the group consisting of hydrogen, halo, C 1 -C 12 alkyl, and C 1 -C 12 alkoxy;
  • R 2 , R 3 , R 4 , R 4a , R 4b , R 5 , R 5b , R 6b , and R 7b are each independently selected from the group consisting of hydrogen, halo, C 1 -C 12 alkyl, C 1 -C 12 alkoxy, C 1 -C 12 alkanoyl, C 1 -C 12 alkenyl, C 1 -C 12 alkynyl, (C 1 -C 12 alkoxy)carbonyl, and (C 1 -C 12 alkylamino)carbonyl;
  • R 6 and R 7 are each independently selected from the group consisting of hydrogen, halo, C 1 -C 12 alkyl, and C 1 -C 12 alkoxy; or, R 6 and R 7 are taken together to form a carbonyl group;
  • R 6a and R 7a are each independently selected from the group consisting of hydrogen, halo, C 1 -C 12 alkyl, and C 1 -C 12 alkoxy; or R 6a and R 7a are taken together to form a carbonyl group;
  • L is one or more, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, amino acids
  • n, p, r, s and t are each independently either 0 or 1.
  • folate refers both individually to folic acid used in forming a conjugate, or alternatively to a folate analog or derivative thereof that is capable of binding to folate or folic acid receptors.
  • the targeting group is a PSMA ligand or inhibitor, such as a derivative of pentanedioic acid of the formula:
  • X is RP(O)(OH)CH 2 — (U.S. Pat. No. 5,968,915); RP(O)(OH)N(R 1 )— (U.S. Pat. No. 5,863,536); RP(O)(OH)O— (U.S. Pat. No. 5,795,877); RN(OH)C(O)Y— or RC(O)NH(OH)Y, wherein Y is —CR 1 R 2 —, —NR 3 — or —O— (U.S. Pat. No.
  • R, R 1 , R 2 , and R 3 are each independently selected from hydrogen, C 1 -C 9 straight or branched chain alkyl, C 2 -C 9 straight or branched chain alkenyl, C 3 -C 8 cycloalkyl, C 5 -C 7 cycloalkenyl, and aryl.
  • each of R, R 1 , R 2 , and R 3 may be optionally substituted, such as with one or more groups selected from C 3 -C 8 cycloalkyl, C 5 -C 7 cycloalkenyl, halo, hydroxy, nitro, trifluoromethyl, C 1 -C 6 straight or branched chain alkyl, C 2 -C 6 straight or branched chain alkenyl, C 1 -C 4 alkoxy, C 2 -C 4 alkenyloxy, phenoxy, benzyloxy, amino, aryl.
  • aryl is selected from 1-naphthyl, 2-naphthyl, 2-indolyl, 3-indolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, benzyl, and phenyl, and in each case aryl may be optionally substituted with one or more, illustratively with one to three, groups selected from halo, hydroxy, nitro, trifluoromethyl, C 1 -C 6 straight or branched chain alkyl, C 2 -C 6 straight or branched chain alkenyl, C 1 -C 4 alkoxy, C 2 -C 4 alkenyloxy, phenoxy, benzyloxy, and amino.
  • R is not hydrogen.
  • PSMA ligands include 2-[[methylhydroxyphosphinyl]methyl]pentanedioic acid; 2-[[ethylhydroxyphosphinyl]methyl]pentanedioic acid; 2-[[propylhydroxyphosphinyl]methyl]pentanedioic acid; 2-[[butylhydroxyphosphinyl]methyl]pentanedioic acid; 2-[[cyclohexylhydroxyphosphinyl]methyl]pentanedioic acid; 2-[[phenylhydroxyphosphinyl]methyl]pentanedioic acid; 2-[[2-(tetrahydrofuranyl)hydroxyphosphinyl]methyl] pentanedioic acid; 2-[[[(2-tetrahydropyranyl)hydroxyphosphinyl]methyl] pentanedioic acid; 2-[[[(2-tetrahydropyranyl)hydroxyphosphinyl]methyl] pentane
  • PSMA ligands include N-[methylhydroxyphosphinyl]glutamic acid; N-[ethylhydroxyphosphinyl]glutamic acid; N-[propylhydroxyphosphinyl]glutamic acid; N-[butylhydroxyphosphinyl]glutamic acid; N-[phenylhydroxyphosphinyl]glutamic acid; N-[(phenylmethyl)hydroxyphosphinyl]glutamic acid; N-[((2-phenylethyl)methyl)hydroxyphosphinyl]glutamic acid; and N-methyl-N-[phenylhydroxyphosphinyl]glutamic acid.
  • PSMA ligands include 2-[[methylhydroxyphosphinyl]oxy]pentanedioic acid; 2-[[ethylhydroxyphosphinyl]oxy]pentanedioic acid; 2-[[propylhydroxyphosphinyl]oxy]pentanedioic acid; 2-[[butylhydroxyphosphinyl]oxy]pentanedioic acid; 2-[[phenylhydroxyphosphinyl]oxy]pentanedioic acid; 2-[[((4-pyridyl)methyl)hydroxyphosphinyl]oxy]pentanedioic acid; 2-[[((2-pyridyl)methyl)hydroxyphosphinyl]oxy]pentanedioic acid; 2-[[[(phenylmethyl)hydroxyphosphinyl]oxy]pentanedioic acid; and 2-[[[((2-phenyleth
  • PSMA ligands include 2-[[(N-hydroxy)carbamoyl]methyl]pentanedioic acid; 2-[[(N-hydroxy-N-methyl)carbamoyl]methyl]pentanedioic acid; 2-[[(N-butyl-N-hydroxy) carbamoyl]methyl]pentanedioic acid; 2-[[(N-benzyl-N-hydroxy)carbamoyl]methyl]pentanedioic acid; 2-[[(N-hydroxy-N-phenyl)carbamoyl]methyl]pentanedioic acid; 2-[[(N-hydroxy-N-2-phenylethyl)carbamoyl]methyl]pentanedioic acid; 2-[[[(N-ethyl-N-hydroxy) carbamoyl]methyl]pentanedioic acid; 2-[[[(N-ethyl-N-hydroxy) carbamoy
  • PSMA ligands include 2-[(sulfinyl)methyl]pentanedioic acid; 2-[(methylsulfinyl)methyl]pentanedioic acid; 2-[(ethylsulfinyl)methyl]pentanedioic acid; 2-[(propylsulfinyl)methyl]pentanedioic acid; 2-[(butylsulfinyl)methyl]pentanedioic acid; 2-[(phenylsulfinyl]methyl]pentanedioic acid; 2-[[(2-phenylethyl)sulfinyl]methyl]pentanedioic acid; 2-[[[(3-phenylpropyl)sulfinyl]methyl]pentanedioic acid; 2-[[[(4-pyridyl)sulfinyl]methyl]
  • PSMA ligands include
  • the PSMA ligand is a urea of two amino acids.
  • the amino acids include one or more additional carboxylic acids.
  • the amino acids include one or more additional phosphoric, phosphonic, phosphinic, sulfinic, sulfonic, or boronic acids.
  • the amino acids include one or more thiol groups or derivatives thereof.
  • the amino acids include one or more carboxylic acid bioisosteres, such as tetrazoles and the like.
  • the PSMA ligand is a compound of the formula:
  • the binding agent is a urea of an amino dicarboxylic acid, such as aspartic acid, glutamic acid, and the like, and another amino dicarboxylic acid, or an analog thereof, such as a binding agent of the formulae
  • Q is a an amino dicarboxylic acid, such as aspartic acid, glutamic acid, or an analog thereof
  • n and m are each independently selected from an integer between 1 and about 6, and (*) represents the point of attachment for the linker L.
  • the PSMA ligand is a compound of the formulae:
  • the PSMA ligand is 2-[3-(1-Carboxy-2-mercapto-ethyl)-ureido]-pentanedioic acid (MUPA) or 2-[3-(1,3-Dicarboxy-propyl)-ureido]-pentanedioic acid (DUPA).
  • MUPA 2-[3-(1-Carboxy-2-mercapto-ethyl)-ureido]-pentanedioic acid
  • DUPA 2-[3-(1,3-Dicarboxy-propyl)-ureido]-pentanedioic acid
  • PSMA ligands include peptide analogs such as quisqualic acid, aspartate glutamate (Asp-Glu), Glu-Glu, Gly-Glu, ⁇ -Glu-Glu, beta-N-acetyl-L-aspartate-L-glutamate ( ⁇ -NAAG), and the like.
  • the PSMA ligand comprises a urea or thiourea of lysine and an amino acid, or one or more carboxylic acid derivatives thereof, including, but not limited to ureas or thioureas of lysine and aspartic acid, or glutamic acid, or homoglutamic acid.
  • the PSMA ligand comprises a urea or thiourea of L-lysine and L-glutamate.
  • the PSMA ligand comprises a compound selected from the following
  • the PSMA ligand comprises the following
  • a method for diagnosing and/or monitoring a disease or disease state where the method comprises the steps of administering to a patient being evaluated for the disease state an effective amount of a conjugate of the general formula B-L-P.
  • the method includes allowing sufficient time for the conjugate to bind to the target tissue, and diagnosing and/or monitoring the disease or disease state extra-corporeally, such as by using positron emission tomography.
  • the radionuclide may include a positron-emitting isotope having a suitable half-life and toxicity profile.
  • the radioisotope has a half-life of more than 30 minutes, more than 70 minutes, more than 80 minutes, more than 90 minutes, more than 100 minutes, less than 8 hours, less than 6 hours, less than 4 hours, or less than 3 hours.
  • the radioisotope has a half-life of about 30 minutes to about 4 hours, about 70 minutes to about 4 hours, about 80 minutes to about 4 hours, about 90 minutes to about 4 hours, about 100 minutes to about 4 hours, about 30 minutes to about 6 hours, about 70 minutes to about 6 hours, about 80 minutes to about 6 hours, about 90 minutes to about 6 hours, about 100 minutes to about 6 hours, about 30 minutes to about 8 hours, about 70 minutes to about 8 hours, about 80 minutes to about 8 hours, about 90 minutes to about 8 hours, or about 100 minutes to about 8 hours.
  • the radionuclide may include one or more positron-emitting isotopes, such as but not limited to isotopes selected from 89 Zr, 45 Ti, 51 Mn, 64 Cu, 63 Zn, 82 Rb, 68 Ga, 66 Ga, 11 C, 13 N, 15 O, 124 I, 34 Cl, and 18 F.
  • the radionuclide is a halide, such as a positron-emitting halide.
  • the radionuclide is a metal ion, such as a positron-emitting metal ion.
  • the radionuclide is a gallium ion, such as a positron-emitting gallium ion.
  • the radionuclide is selected from 89 Zr, 64 Cu, 68 Ga, 66 Ga, 124 I, and 18 F.
  • the radioisotope is selected from 89 Zr, 64 Cu, 68Ga, 124 I, and 18 F.
  • the radioisotope is 68 Ga, or 89 Zr, or 18 F.
  • the radioisotope is 68 Ga.
  • the radioisotope is 18 F.
  • the radioisotope is 89 Zr.
  • the radioisotope is 64 Cu.
  • the fluorine isotopes described herein may be selected from various isotopic combinations of 18 F and 19 F. It is understood that factors that may be included during selection of a suitable isotope include sufficient half-life of the positron-emitting isotope to permit preparation of a diagnostic composition in a pharmaceutically acceptable carrier prior to administration to the patient, and sufficient remaining half-life to yield sufficient activity to permit extra-corporeal measurement by a PET scan. Further, a suitable isotope should have a sufficiently short half-life to limit patient exposure to unnecessary radiation. In an illustrative embodiment, 18 F, having a half-life of 110 minutes, provides adequate time for preparation of the diagnostic composition, as well as an acceptable deterioration rate. Further, on decay 18 F is converted to 18 O.
  • Illustrative positron-decaying isotopes having suitable half-lives include 34 Cl, half-life about 32 minutes; 45 Ti, half-life about 3 hours; 51 Mn, half-life about 45 minutes; 61 Cu, half-life about 3.4 hours; 63 Zn, half-life about 38 minutes; 82 Rb, half-life about 2 minutes; 68 Ga, half-life about 68 minutes, 66 Ga, half-life about 9.5 hours, 11 C, half-life about 20 minutes, 15 O, half-life about 2 minutes, 13 N, half-life about 10 minutes, or 18 F, half-life about 110 minutes.
  • the radionuclide is a radiotherapy agent.
  • Illustrative radionuclides for radiotherapy include isotopes of lutetium such as 177 Lu, isotopes of yttrium, such as 90 Y, isotopes of copper, such as 67 Cu and 64 Cu, and the like.
  • the radionuclide may be covalently attached to the conjugate, such as to an aryl or heteroaryl aromatic group, including benzamidyl, benzylic, phenyl, pyridinyl, pyrimidinyl, pyridazinyl, naphthyl, benzothiazolyl, benzimizolyl, benzoxazolyl, and like groups.
  • the radioisotope is 18 F and the radionuclide includes an aryl group to which the radioisotope is covalently attached.
  • the radionuclide may be non-covalently attached to the conjugate, such as within a chelate.
  • the methods may also be used in combination with any other methods of cancer diagnosis already developed and known in the art, including methods using other already developed diagnostic agents and utilizing x-ray computed tomography (CT), magnetic resonance imaging (MRI), functional magnetic resonance imaging (fMRI), ultrasound, and single photon emission computed tomography (SPECT).
  • CT computed tomography
  • MRI magnetic resonance imaging
  • fMRI functional magnetic resonance imaging
  • SPECT single photon emission computed tomography
  • each of the processes and synthetic methods described herein either substantially complete fluorination, or alternatively only partial fluorination may be desired. Accordingly, the processes and synthetic methods described herein may be performed in various alternative embodiments. It is therefore understood that in those aspects where only partial fluorination is desired, the processes and syntheses described herein may be performed with less than stoichiometric amounts of fluorinating agent. Similarly, it is understood that in certain applications of the methods described herein, each of the processes and synthetic methods described herein either substantially complete radiofluorination, or alternatively only partial radiofluorination may be desired. Accordingly, the processes and synthetic methods described herein may be performed in various alternative embodiments. It is therefore understood that in those aspects where only partial radiofluorination is desired, the processes and syntheses described herein may be performed with less than stoichiometric amounts of radiofluorination agent, where the balance is optionally 19 F.
  • N10-TFA-Pteroic Acid was provided by Endocyte, Inc.
  • High-performance liquid chromatography (HPLC) analysis and purification of the DUPA-NOTA precursor were performed on an Agilent G6130B instrument.
  • the radioactive HPLC was performed with a ⁇ -counter using a Xselect CSH C18 (250 ⁇ 10 mm) column and MeCN and 0.1% Formic Acid as mobile phases.
  • C-NETA tert-Butyl [2-Hydroxy-1-(4-nitrobenzyl)ethyl]carbamate (QC04011) was prepared from the commercially available methyl 2-amino-3-(4-nitrophenyl)propanoate through NaBH 4 reduction and Boc- protection. Successive Dess-Martin oxidation and reductive amination with QC04001 afforded tris-Boc protected compound QC04013, which was transformed to QC04014 after Boc- deprotection in 4 M HCl in dioxane. Treatment of QC04014 with tert-butyl bromoacetate, followed by hydrogenolysis of the NO 2 group provided QC04016. Further reaction of QC04016 with succinic anhydride provided the bifunctional C-NETA (QC04018) as the corresponding tert-butyl ester.
  • reaction was quenched by addition of a basic aq Na 2 S 2 O 3 solution (50/50, v/v of aq Na 2 S 2 O 3 and aq Na 2 HCO 3 ), and the resulting mixture was vigorously stirred for 15 min. After extraction with CH 2 Cl 2 (3 ⁇ ), the organic phases were washed successively with water and brine, dried over Na 2 SO 4 , filtered and concentrated in vacuo to provide QC04012, which was used without further purification.
  • a basic aq Na 2 S 2 O 3 solution 50/50, v/v of aq Na 2 S 2 O 3 and aq Na 2 HCO 3
  • Fmoc-Lys-resin 1.0 g, 0.5 mmol
  • DMF 3 ⁇ 10 ml
  • Initial Fmoc deprotection was performed using 20% piperidine in DMF (3 ⁇ 10 ml) solution for 10 mins per cycle.
  • a Kaiser test was done to determine reaction completion.
  • an amino acid solution 2.0 eq.
  • PyBOP 2.0 eq.
  • DIPEA 3.0 eq.
  • EXAMPLE Pte- ⁇ Glu-Lys-NOTA.
  • EC 1777 30.5 mg, 0.054 mmol, 1.0 eq.
  • 1,1,3,3-tetramethylguanidine 13.45 ⁇ l, 0.107 mmol, 2.0 eq.
  • DMSO 2.5 ml
  • DIPEA 0.19 ml, 1.07 mmol, 20 eq.
  • Pte- ⁇ Glu-Lys-NOTA -Al-18F is prepared by reaction of Pte- ⁇ Glu-Lys-NOTA with Al 18 F3.3H 2 O (1 step method) or with AlCl 3 .3H 2 O followed by reaction with Na 18 F (2 step method) using published processes.
  • Resin cleavage/global tert-butyl ester deprotection was performed with a cocktail consisting of 95% CF 3 CO 2 H, 2.5% H 2 O and 2.5% triisopropylsilane.
  • the cleavage cocktail (10 ml) was poured onto the resin and bubbled with Argon for 60 mins, followed by filtration into a clean flask. Further cleavage was performed twice successively with fresh cleavage cocktail for 20 mins of bubbling.
  • the combined filtrate was poured onto cold diethyl ether, the precipitate formed was collected by centrifugation at 4000 rpm for 5 mins (3 ⁇ ). The precipitate was obtained following decanting and drying of the solid under vacuum.
  • Pte- ⁇ Glu-Asp-Arg-Arg-Lys-Bn-NOTA 6 (EC2218).
  • Pte- ⁇ Glu-Asp-Arg-Arg-Lys-Bn-NOTA, EC2218 was prepared in 18% yield according to the process described for folate-peptide-NOTA, 4.
  • the general procedure described for the synthesis of resin bound folate-peptide resin 1 was followed for the coupling of Fmoc-L-Arg(Pbf)-OH, Fmoc-Glu-O t Bu, and N10-TFA-Pte-OH to Fmoc-L-Lys(Mtt)-Wang resin.
  • Pte- ⁇ Glu-Arg-Lys-Bn-NOTA 8 (EC2219).
  • Pte- ⁇ Glu-Arg-Lys-Bn-NOTA, EC2219 was prepared in 20% yield according to the process described for folate-peptide-NOTA, 4.
  • [M+H]+ Calculated 1178.51, found 1178.7
  • Resin cleavage/global tert-butyl ester deprotection was performed with a cocktail consisting of 95% CF 3 CO 2 H, 2.5% H 2 O and 2.5% triisopropylsilane.
  • the cleavage cocktail (10 ml) was poured onto the resin and bubbled with Argon for 1 hr, followed by filtration into a clean flask. Further cleavage was performed twice successively with fresh cleavage cocktail for 10 mins of bubbling.
  • the combined filtrate was poured onto cold diethyl ether, the precipitate formed was collected by centrifugation at 4000 rpm for 5 mins (3 ⁇ ). The precipitate was obtained following decanting and drying of the solid under vacuum.
  • FA-NOTA-Al— 18 F Radiotracer[2]. Two methods for the formation of FANOTA-Al— 18 F are described herein. Conditions including the pH value, concentration of the substrates and temperature for the chelating reaction with 18 F—Al can be varied. The general methods for FA-NOTA-Al— 18 F are described as followed:
  • the crude material was loaded to a cartridge, and the radiotracer was eluted into vial. After sterile filtration and being diluted to appropriate radioactivity (5-10 mCi) and specific activity (>1 Ci/ ⁇ mol), the radiotracer was ready for in vivo PET imaging study.
  • EXAMPLE Standard Protocol for the Formulation of Folate-NOTA-Al 18 F Radiotracer.
  • the resin containing 18 F was first washed with 1.5 mL of ultrapure water, and then 18 F was eluted out from resin by using 1.0 mL of 0.4 M KHCO 3 solution.
  • 100 ⁇ L of the eluting solution containing 18 F was added to a stem vial charged with 10 ⁇ L acetic acid, 25 ⁇ L AlCl 3 (2 mM in 0.1 M NaOAc pH 4 buffer) and 125 ⁇ L 0.1 M NaOAc pH 4 buffer.
  • the whole mixture was incubated for 2 mM before 0.25 mg folate-NOTA precursor (1) in 125 ⁇ L of 0.1 M NaOAc pH 4 buffer was transferred to the same stem vial.
  • the reaction was immediately heated to 100° C. for 15 min.
  • radiochemcial synthesis of FA-PEG 12 -NOTA-Al— 18 F radiotracer was accomplished in ⁇ 35 mM with a specific activity (SA) of 49 ⁇ 17.1 GBq/ ⁇ mol. Although the radiochemical purity is excellent, 100% after radioactive HPLC purification, the total radiochemical yield (RCY) is relatively low, ⁇ 25-30%. After sterile filtration and appropriate dilution in isotonic saline to the desired radioactivity, the FA-PEG 12 -NOTA-Al— 18 F radiotracer was ready for PET imaging study.
  • C-NETA and folate-C-NETA A PyBOP promoted coupling between QC04018 and compound 6, followed by deprotection of tert-butyl ester with TFA, provided folate-C-NETA.
  • the folate-C-NETA is used to evaluate the labeling efficiency with Al 18 F and 68 Ga and evaluate the in vivo PET imaging.
  • EXAMPLE General procedure for the one-pot 19 F-introduction and deprotection. 8.3 ⁇ L of freshly prepared KF-Kryptofix (1/1.5) (0.0012 mmol, 0.144 M) solution was azeotropically dried with CH 3 CN at 90-100° C., to which 1.2 mg (0.0012 mmol, 1.0 equiv.) QC07005 in 50 ul of anhydrous DMSO was added with a concentration of precursor at 0.024 M. The resulting mixture was immediately immersed into an oil bath preheated to 70-75° C. and kept at 70-75° C. for 10 min.
  • the Cbz protected amine was transferred to a round bottom flask with 10% Pd/C (10% wt eq), dissolved in MeOH (30 ml) under Hydrogen atmosphere (latm) and stirred for 3 hr. Upon completion, the reaction mixture was filtered through celite and the solvent was removed via reduced pressure to yield the crude amine. The amine was taken up in CH 2 Cl 2 (30 ml) under Argon atmosphere and chilled to 0° C. To the chilled solution was added 4-nitrophenyl chloroformate (2.2 g, 10.9 mmol, 1.3 eq) and DIPEA (6.0 ml, 33.6 mmol, 4 eq) subsequently and stirred for 2 hr at room temperature.
  • reaction mixture was quenched with saturated NH 4 Cl and extract three times with ethyl acetate.
  • the organic extracts were combined, dried over Na 2 SO 4 , filtered, and solvent was removed under vacuum and purified using silica gel chromatography to yield the desired activated amine, EC1380 (2.54 g, 46%).
  • the resin bound penta-peptide was subjected to standard Fmoc deprotection, washings and Kaiser test. Following another DMF wash (3 ⁇ 10 ml); an EC1380 solution (2.0 eq.) in DMF, and DIPEA (3.0 eq.) were added to the vessel and the solution bubbled with Argon for 2 hour. The coupling solution was filtered, the resin was washed with DMF (3 ⁇ 10 ml) and i-PrOH (3 ⁇ 10 ml) and a Kaiser test was done to assess reaction completion.
  • Reagents and conditions (a) (i) 20% piperidine/DMF, room temperature, 10 min; (ii) Fmoc-Arg(Boc)2-OH, HBTU, HOBt, DMF-DIPEA, 2 h. (b) (i) 20% piperidine/DMF, room temperature, 10 min; (ii) Fmoc-Phe-OH, HBTU, HOBt, DMF-DIPEA, 2 h. (c) (i) 20% piperidine/DMF, room temperature, 10 min; (ii) Fmoc-8-amino-octanoic (EAO) acid, HBTU, HOBt, DMF/DIPEA, 2 h.
  • EAO Fmoc-8-amino-octanoic
  • DUPA-EAOA-Phe-Arg-Lys-NH 2 -NOTA is dissolved in 2 mM NaOAc (pH 4.5), and treated with AlCl 3 .3H 2 O (1.5 eq.). The pH is adjusted to 4.5-5.0, and the reaction mixture is refluxed for 15-30 mM with the pH kept at 4.5-5.0. The crude material is purified by RP-HPLC to afford the DUPA-EAOA-Phe-Arg-Lys-NH 2 -NOTA-Al—OH intermediate ready for 18 F-labeling.
  • DUPA-EAOA-Phe-Arg-Lys-NH 2 -NOTA-Al—OH is treated with Na 18 F saline solution and ethanol (1/1, v/v), and the whole mixture is heated at 100-110° C. for 15 min. After cooling to room temperature, the crude material is loaded to a cartridge, and the radiotracer eluted into vial. After sterile filtration and being diluted to appropriate radioactivity (5-10 mCi) and specific activity (>1 Ci/ ⁇ mol), the radiotracer is ready for use in in vivo PET imaging.
  • Reagents and conditions (a) Fmoc-Phe-OH, HBTU, HOBt, DMF/DIPEA, 2 h. (b) (i) 20% piperidine/DMF, room temperature, 10 min; (ii) Fmoc-Phe-OH, HBTU, HOBt, DMF/DIPEA, 2 h. (c) (i) 20% piperidine/DMF, room temperature, 10 min; (ii) Fmoc-8-amino-octanoic (EAO) acid, HBTU, HOBt, DMF/DIPEA, 2 h.
  • EAO Fmoc-8-amino-octanoic
  • EXAMPLE Solid Phase Peptide Synthesis (SPPS) of DUPA-EAOA-Phe-Phe-EDA-NH 2 .[2, 3].
  • SPPS Solid Phase Peptide Synthesis
  • DUPA-EAOA-Phe-Phe-EDA-NH 2 is prepared.
  • the commercially available Trt-EDA resin was swollen with DCM (3 mL) followed by dimethyl formamide (DMF, 3 mL), to which a solution of Fmoc-Phe-OH (2.5 equiv), HBTU (2.5 equiv), HOBt (2.5 equiv), and DIPEA (4.0 equiv) in DMF was added.
  • EXAMPLE Radiochemical Synthesis of DUPA-EAOA-Phe-Arg-Lys-NOTA- 64 Cu Radiotracer. NOTA based chelators have also been reported and employed in the formulation of NOTA- 64/67 Cu for nuclear medicine/radiotherapy.[14-16] The corresponding DUPA-NOTA- 64 Cu was prepare for the dual purpose of imaging and therapy, also referred to as theranostics. DUPA-EAOA-Phe-Arg-Lys-NOTA- 64 Cu was prepared according a standard protocol with minor modifications.
  • EXAMPLE General procedure for 68 Ga labeling: 68 Ga was eluted from the 68 Ge/ 68 Ga generator with 0.1N HCl. A predetermined amount of 68 Ga in 0.1N HCl was added to a DUPA-NOTA solution in acetate buffer (pH 4.8). The labeling mixture was incubated at room temperature, and labeling efficiencies were checked by radioactive HPLC. The radiolabeled product was purified by radioactive HPLC and the DUPA-NOTA- 68 Ga peak sample was collected. After sterile filtration and being diluted to appropriate radioactivity (5-10 mCi) and specific activity (>1 Ci/ ⁇ mol), the radiotracer was ready for in vivo PET imaging study.
  • C-NETA a NOTA derivative
  • C-NETA also reportedly chelates the commonly used radiotherapeutic nuclides, such as 177 Lu and 90 Y, with high labeling efficiency.[18]
  • the radionuclide is a metal or metal halide, such as Al 18 F, 68 Ga, 177 Lu or 90 Y.
  • EXAMPLE A PyBOP promoted coupling between QC04018 and QC08008, followed by deprotection of tert-butyl ester with TFA provides DUPA-C-NETA.
  • DUPA-C-NETA is used to evaluate the labeling efficiency to Al 18 F, 177 Lu and 90 Y, and evaluate the in vivo PET imaging and radiotherapy.
  • EXAMPLE The specificity of the radionuclide containing conjugates binding to FR is evaluated against KB xenografts homogenates and Cal51 xenografts homogenates. Concentration dependent binding was evaluated for 18 F-AIF-QC07017 and 18 F-AIF-QC07043, and separated into specific and non-specific binding. Significant non-specific binding was not observed in KB homogenates.
  • EXAMPLE ⁇ PET imaging was performed on nude mice bearing KB tumor xenografts under baseline and competed conditions to evaluate the in vivo binding specificity of 18 F-AIF-QC07017 (2) to FR. Nude mice bearing KB tumor xenografts on their left shoulder were injected with 0.30-0.40 mCi (2). The competed group received 100 ⁇ g of folic acid 10 min before the i.v. injection of (2), and the treatment group was injected with a corresponding volume of phosphate buffer. Time course inspection of PET images obtained at various time points revealed that the data acquired in 60-90 min post tracer injection gave the best visual PET imaging.
  • the KB tumors were clearly visualized in the treated group, whereus the uptake of (2) was completely inhibited by competing with folic acid, supporting a high specificity of (2) binding to FR in vivo.
  • the high radioactivity found in kidneys was due to the uptake mediated by FR that is expressed in the proximal tubule cells in kidneys and the potential accumulation of radiotracer via renal excretion, which was further supported by the biodistribution studies described herein.
  • significant uptake in other organs was not observed. A significant blocking effect in liver uptake was observed in under competed conditions.
  • EXAMPLE Ex vivo biodistribution study of compounds described herein under both baseline and competed conditions in nude mice bearing KB tumor xenografts on their left shoulder demonstrates a high and specific uptake in FR(+) tumors. Radiotracer levels of 18 F-AIF-QC07017 and 18 F-AIF-QC07043 were determined in whole blood, plasma, heart, kidney, liver, lung, muscle, spleen, KB xenograft tumor tissues and A549 xenograft tumor tissues ( FIG. 1A , FIG. 1B , and FIG. 1C ). The highest signal was observed in the kidneys. Accumulation was observed to a substantially less extent in the liver.
  • the FR specificity of 18 F-AIF-QC07017 and 18 F-AIF-QC07043 was comparable to etarfolatide (EC20), a compound in clinical trials, in both KB xenograft tumor tissues and A549 xenograft tumor tissues.
  • PC3 is a PSMA ( ⁇ ) cell line
  • LnCap is a PSMA (+) cell line
  • PIP-PC3 is a transfect cell line with higher PSMA expression.
  • Uptake of 68 Ga-QC08009 by PC3 cells was minimal, and did not change when competed.
  • Uptake of 68 Ga-QC08009 by LnCaP and PIP-PC3 was substantial, with PIP-PC3 cells showing the highest uptake.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Physics & Mathematics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Optics & Photonics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Epidemiology (AREA)
  • Hematology (AREA)
  • Immunology (AREA)
  • Urology & Nephrology (AREA)
  • Molecular Biology (AREA)
  • Biomedical Technology (AREA)
  • Cell Biology (AREA)
  • General Physics & Mathematics (AREA)
  • Microbiology (AREA)
  • Pathology (AREA)
  • Food Science & Technology (AREA)
  • Biotechnology (AREA)
  • Analytical Chemistry (AREA)
  • Biochemistry (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicinal Preparation (AREA)
  • Peptides Or Proteins (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Nuclear Medicine (AREA)
US15/035,936 2013-11-14 2014-11-13 Compounds for Positron Emission Tomography Abandoned US20160287731A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US15/035,936 US20160287731A1 (en) 2013-11-14 2014-11-13 Compounds for Positron Emission Tomography

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US201361904387P 2013-11-14 2013-11-14
US201361904400P 2013-11-14 2013-11-14
US201361909822P 2013-11-27 2013-11-27
PCT/US2014/065467 WO2015073678A1 (en) 2013-11-14 2014-11-13 Compounds for positron emission tomography
US15/035,936 US20160287731A1 (en) 2013-11-14 2014-11-13 Compounds for Positron Emission Tomography

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2014/065467 A-371-Of-International WO2015073678A1 (en) 2013-11-14 2014-11-13 Compounds for positron emission tomography

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US16/157,024 Continuation US20190275181A1 (en) 2013-11-14 2018-10-10 Compounds for Positron Emission Tomography

Publications (1)

Publication Number Publication Date
US20160287731A1 true US20160287731A1 (en) 2016-10-06

Family

ID=53058011

Family Applications (3)

Application Number Title Priority Date Filing Date
US15/035,936 Abandoned US20160287731A1 (en) 2013-11-14 2014-11-13 Compounds for Positron Emission Tomography
US16/157,024 Abandoned US20190275181A1 (en) 2013-11-14 2018-10-10 Compounds for Positron Emission Tomography
US17/488,810 Pending US20220125958A1 (en) 2013-11-14 2021-09-29 Compounds for positron emission tomography

Family Applications After (2)

Application Number Title Priority Date Filing Date
US16/157,024 Abandoned US20190275181A1 (en) 2013-11-14 2018-10-10 Compounds for Positron Emission Tomography
US17/488,810 Pending US20220125958A1 (en) 2013-11-14 2021-09-29 Compounds for positron emission tomography

Country Status (14)

Country Link
US (3) US20160287731A1 (ko)
EP (3) EP3069147A4 (ko)
JP (5) JP6464166B2 (ko)
KR (1) KR102457827B1 (ko)
CN (2) CN105849568B (ko)
AU (3) AU2014348601A1 (ko)
BR (1) BR112016010927A2 (ko)
CA (1) CA2930581A1 (ko)
EA (1) EA035171B1 (ko)
IL (2) IL245612A0 (ko)
MX (2) MX2016006219A (ko)
SG (1) SG10201803618RA (ko)
TW (1) TWI657827B (ko)
WO (1) WO2015073678A1 (ko)

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10046054B2 (en) 2007-08-17 2018-08-14 Purdue Research Foundation PSMA binding ligand-linker conjugates and methods for using
US10398791B2 (en) 2013-10-18 2019-09-03 Deutsches Krebsforschungszentrum Labeled inhibitors of prostate specific membrane antigen (PSMA), their use as imaging agents and pharmaceutical agents for the treatment of prostate cancer
WO2019246445A1 (en) * 2018-06-20 2019-12-26 The Research Foundation For The State University Of New York Triazamacrocycle-derived chelator compositions for coordination of imaging and therapy metal ions and methods of using same
US10557128B2 (en) 2010-02-25 2020-02-11 Purdue Research Foundation PSMA binding ligand-linker conjugates and methods for using
US10898596B2 (en) 2015-01-07 2021-01-26 Endocyte, Inc. Conjugates for imaging
US10912840B2 (en) 2012-11-15 2021-02-09 Endocyte, Inc. Conjugates for treating diseases caused by PSMA expressing cells
WO2022006007A1 (en) * 2020-06-29 2022-01-06 The General Hospital Corporation Methods for imaging bacterial infections
CN114028590A (zh) * 2021-11-18 2022-02-11 北京大学 颗粒酶b靶向配合物、放射性药物及其制备方法和应用
WO2022204065A1 (en) * 2021-03-20 2022-09-29 The Research Foundation For The State University Of New York Iron(iii) macrocyclic complexes with mixed hyroxyl pendants as mri contrast agents
WO2022219569A1 (en) * 2021-04-16 2022-10-20 Novartis Ag Folate receptor-targeted radiotherapeutic agents and their use

Families Citing this family (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EA037512B1 (ru) 2015-09-30 2021-04-06 Дойчес Кребсфоршунгсцентрум Улучшенные ингибиторы простатического специфического мембранного антигена (псма), меченные 18f, и их применение в качестве визуализирующих агентов при раке простаты
US10688200B2 (en) * 2015-12-31 2020-06-23 Five Eleven Pharma Inc. Urea-based prostate specific membrane antigen (PSMA) inhibitors for imaging and therapy
WO2017117687A1 (en) 2016-01-10 2017-07-13 British Columbia Cancer Agency Branch 18/19f-labelled compounds which target the prostate specific membrane antigen
US10239891B2 (en) 2017-05-15 2019-03-26 Indicator Systems International, Inc. Compositions to detect remnant cancer cells
WO2018026965A1 (en) 2016-08-02 2018-02-08 Isi Life Sciences, Inc. Compositions and methods for detecting cancer cells in a tissue sample
WO2018026538A1 (en) * 2016-08-02 2018-02-08 ISI Life Sciences Inc. Novel scaffolds for intracellular compound delivery for the detection of cancer cells
JP7231536B2 (ja) 2016-08-10 2023-03-01 キャンサー ターゲテッド テクノロジー エルエルシー キレート化されたｐｓｍａ阻害剤
WO2018098390A1 (en) * 2016-11-23 2018-05-31 Cancer Targeted Technology Llc Albumin-binding psma inhibitors
CN106632341A (zh) * 2016-12-27 2017-05-10 天津阿尔塔科技有限公司 一种d‑叶酸的合成方法
US10753942B2 (en) 2017-05-15 2020-08-25 Indicator Systems International, Inc. Methods to detect remnant cancer cells
CN108997170B (zh) * 2018-08-07 2021-04-06 贾国苓 一种易碱解多羧基螯合物及其制备工艺
WO2020108753A1 (en) * 2018-11-28 2020-06-04 ITM Isotopen Technologien München AG Novel tumor antigen binding agents and uses thereof
CN114401947A (zh) 2019-06-21 2022-04-26 省卫生服务机构 靶向前列腺特异性膜抗原的放射性标记化合物
CN110627837A (zh) * 2019-09-10 2019-12-31 齐鲁工业大学 一种检测一氧化碳的金属有机框架材料及制备方法和应用
WO2023164161A2 (en) * 2022-02-24 2023-08-31 Purdue Research Foundation Conjugates, compositions, and methods for hydroxyapatite-targeted imaging and therapy

Family Cites Families (38)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5795877A (en) 1996-12-31 1998-08-18 Guilford Pharmaceuticals Inc. Inhibitors of NAALADase enzyme activity
US5902817A (en) 1997-04-09 1999-05-11 Guilford Pharmaceuticals Inc. Certain sulfoxide and sulfone derivatives
US5672592A (en) 1996-06-17 1997-09-30 Guilford Pharmaceuticals Inc. Certain phosphonomethyl-pentanedioic acid derivatives thereof
US5863536A (en) 1996-12-31 1999-01-26 Guilford Pharmaceuticals Inc. Phosphoramidate derivatives
US5962521A (en) 1997-04-04 1999-10-05 Guilford Pharmaceuticals Inc. Hydroxamic acid derivatives
US6093382A (en) * 1998-05-16 2000-07-25 Bracco Research Usa Inc. Metal complexes derivatized with folate for use in diagnostic and therapeutic applications
AUPQ014799A0 (en) * 1999-05-04 1999-05-27 Access Pharmaceuticals Australia Pty Limited Amplification of folate-mediated targeting to tumor cells using polymers
US6692724B1 (en) * 1999-10-25 2004-02-17 Board Of Regents, The University Of Texas System Ethylenedicysteine (EC)-drug conjugates, compositions and methods for tissue specific disease imaging
JP5448284B2 (ja) * 2000-06-02 2014-03-19 ボード・オブ・リージエンツ，ザ・ユニバーシテイ・オブ・テキサス・システム エチレンジシステイン（ｅｃ）−薬物結合体
DE60231868D1 (de) 2001-04-24 2009-05-20 Purdue Research Foundation Folat-mimetika und deren folatrezeptorbindende konjugate
CN101648028B (zh) * 2002-05-06 2012-11-21 恩多塞特公司 维生素-定向的显象剂
US7597876B2 (en) * 2007-01-11 2009-10-06 Immunomedics, Inc. Methods and compositions for improved F-18 labeling of proteins, peptides and other molecules
CN100381177C (zh) * 2003-01-27 2008-04-16 恩多塞特公司 维生素受体结合递药缀合物
WO2004069159A2 (en) 2003-01-27 2004-08-19 Endocyte, Inc. Vitamin receptor binding drug delivery conjugates
US20050085417A1 (en) * 2003-10-16 2005-04-21 Thomas Jefferson University Compounds and methods for diagnostic imaging and therapy
CN101098854B (zh) 2004-07-23 2012-12-05 恩多塞特公司 二价连接体及其轭合物
EP1904183B1 (en) * 2005-07-05 2014-10-15 Purdue Research Foundation Pharmaceutical composition for the treatment of osteoarthritis
RU2470668C2 (ru) 2005-08-19 2012-12-27 Эндосайт, Инк. Конъюгаты лиганда с несколькими лекарственными средствами
US8926945B2 (en) * 2005-10-07 2015-01-06 Guerbet Compounds comprising a biological target recognizing part, coupled to a signal part capable of complexing gallium
US9265746B2 (en) * 2006-05-31 2016-02-23 Merck & Cie Method for cell-specific targeting
US10925977B2 (en) * 2006-10-05 2021-02-23 Ceil>Point, LLC Efficient synthesis of chelators for nuclear imaging and radiotherapy: compositions and applications
AU2007343600B2 (en) * 2007-01-11 2012-06-28 Immunomedics, Inc. Methods and compositions for improved F-18 labeling of proteins, peptides and other molecules
WO2008098112A2 (en) * 2007-02-07 2008-08-14 Purdue Research Foundation Positron emission tomography imaging method
US20100104626A1 (en) * 2007-02-16 2010-04-29 Endocyte, Inc. Methods and compositions for treating and diagnosing kidney disease
EP3569251A1 (en) 2007-06-25 2019-11-20 Endocyte, Inc. Conjugates containing hydrophilic spacer linkers
US9044468B2 (en) * 2007-06-26 2015-06-02 The Johns Hopkins University Labeled inhibitors of prostate specific membrane antigen (PSMA), biological evaluation, and use as imaging agents
PT2187965T (pt) * 2007-08-17 2020-01-17 Purdue Research Foundation Conjugados ligando-ligante de ligação a psma e métodos para utilização
PT2644192T (pt) * 2007-09-28 2017-07-12 Pfizer Direcionamento a células cancerosas utilizando nanopartículas
US8685937B2 (en) * 2008-08-09 2014-04-01 University Of Iowa Research Foundation Nucleic acid aptamers
LT3964502T (lt) * 2009-03-19 2024-08-26 The Johns Hopkins University Junginiai nukreipti į psma ir jų panaudojimas
CA2790577A1 (en) * 2010-02-25 2011-09-01 Purdue Research Foundation Psma binding ligand-linker conjugates and methods for using
US9951324B2 (en) * 2010-02-25 2018-04-24 Purdue Research Foundation PSMA binding ligand-linker conjugates and methods for using
CN101863924B (zh) * 2010-05-17 2012-06-27 北京师范大学 99mTc标记肼基烟酰胺基-二氧辛酰-叶酸配合物及制备方法
EP3505192A1 (en) * 2011-08-05 2019-07-03 Molecular Insight Pharmaceuticals, Inc. Radiolabeled prostate specific membrane antigen inhibitors
US9629918B2 (en) * 2012-02-29 2017-04-25 Purdue Research Foundation Folate receptor alpha binding ligands
WO2014062697A2 (en) * 2012-10-16 2014-04-24 Endocyte, Inc. Drug delivery conjugates containing unnatural amino acids and methods for using
WO2015027205A1 (en) * 2013-08-22 2015-02-26 Robert Doyle Compositions comprising vitamin b12 and intrinsic factor and methods of use thereof
CN103951668A (zh) * 2014-04-25 2014-07-30 广州军区广州总医院 叶酸衍生物的正电子核素标记物及其应用

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Heston US 2008/0311037 *

Cited By (30)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11298341B2 (en) 2007-08-17 2022-04-12 Purdue Research Foundation PSMA binding ligand-linker conjugates and methods for using
US11318121B2 (en) 2007-08-17 2022-05-03 Purdue Research Foundation PSMA binding ligand-linker conjugates and methods for using
US11717514B2 (en) 2007-08-17 2023-08-08 Purdue Research Foundation PSMA binding ligand-linker conjugates and methods for using
US11504357B2 (en) 2007-08-17 2022-11-22 Purdue Research Foundation PSMA binding ligand-linker conjugates and methods for using
US10485878B2 (en) 2007-08-17 2019-11-26 Purdue Research Foundation PSMA binding ligand-linker conjugates and methods for using
US11369590B2 (en) 2007-08-17 2022-06-28 Purdue Research Foundation PSMA binding ligand-linker conjugates and methods for using
US10517957B2 (en) 2007-08-17 2019-12-31 Purdue Research Foundation PSMA binding ligand-linker conjugates and methods for using
US10517956B2 (en) 2007-08-17 2019-12-31 Purdue Research Foundation PSMA binding ligand-linker conjugates and methods for using
US10046054B2 (en) 2007-08-17 2018-08-14 Purdue Research Foundation PSMA binding ligand-linker conjugates and methods for using
US10624971B2 (en) 2007-08-17 2020-04-21 Purdue Research Foundation PSMA binding ligand-linker conjugates and methods for using
US10624970B2 (en) 2007-08-17 2020-04-21 Purdue Research Foundation PSMA binding ligand-linker conjugates and methods for using
US10624969B2 (en) 2007-08-17 2020-04-21 Purdue Research Foundation PSMA binding ligand-linker conjugates and methods for using
US10646581B2 (en) 2007-08-17 2020-05-12 Purdue Research Foundation PSMA binding ligand-linker conjugates and methods for using
US10828282B2 (en) 2007-08-17 2020-11-10 Purdue Research Foundation PSMA binding ligand-linker conjugates and methods for using
US11083710B2 (en) 2007-08-17 2021-08-10 Purdue Research Foundation PSMA binding ligand-linker conjugates and methods for using
US10406240B2 (en) 2007-08-17 2019-09-10 Purdue Research Foundation PSMA binding ligand-linker conjugates and methods for using
US12091693B2 (en) 2010-02-25 2024-09-17 Purdue Research Foundation PSMA binding ligand-linker conjugates and methods for using
US11155800B2 (en) 2010-02-25 2021-10-26 Purdue Research Foundation PSMA binding ligand-linker conjugates and methods for using
US10557128B2 (en) 2010-02-25 2020-02-11 Purdue Research Foundation PSMA binding ligand-linker conjugates and methods for using
US10912840B2 (en) 2012-11-15 2021-02-09 Endocyte, Inc. Conjugates for treating diseases caused by PSMA expressing cells
US10471160B2 (en) 2013-10-18 2019-11-12 Deutsches Krebsforschungszentrum Labeled inhibitors of prostate specific membrane antigen (PSMA), their use as imaging agents and pharmaceutical agents for the treatment of prostate cancer
US10398791B2 (en) 2013-10-18 2019-09-03 Deutsches Krebsforschungszentrum Labeled inhibitors of prostate specific membrane antigen (PSMA), their use as imaging agents and pharmaceutical agents for the treatment of prostate cancer
US11045564B2 (en) 2013-10-18 2021-06-29 Deutsches Krebsforschungszentrum Labeled inhibitors of prostate specific membrane antigen (PSMA) as agents for the treatment of prostate cancer
US11951190B2 (en) 2013-10-18 2024-04-09 Novartis Ag Use of labeled inhibitors of prostate specific membrane antigen (PSMA), as agents for the treatment of prostate cancer
US10898596B2 (en) 2015-01-07 2021-01-26 Endocyte, Inc. Conjugates for imaging
WO2019246445A1 (en) * 2018-06-20 2019-12-26 The Research Foundation For The State University Of New York Triazamacrocycle-derived chelator compositions for coordination of imaging and therapy metal ions and methods of using same
WO2022006007A1 (en) * 2020-06-29 2022-01-06 The General Hospital Corporation Methods for imaging bacterial infections
WO2022204065A1 (en) * 2021-03-20 2022-09-29 The Research Foundation For The State University Of New York Iron(iii) macrocyclic complexes with mixed hyroxyl pendants as mri contrast agents
WO2022219569A1 (en) * 2021-04-16 2022-10-20 Novartis Ag Folate receptor-targeted radiotherapeutic agents and their use
CN114028590A (zh) * 2021-11-18 2022-02-11 北京大学 颗粒酶b靶向配合物、放射性药物及其制备方法和应用

Also Published As

Publication number Publication date
MX2016006219A (es) 2016-10-28
US20190275181A1 (en) 2019-09-12
EA201690862A1 (ru) 2016-12-30
KR102457827B1 (ko) 2022-10-24
JP7299285B2 (ja) 2023-06-27
EP3069147A4 (en) 2017-10-11
WO2015073678A1 (en) 2015-05-21
JP2016540747A (ja) 2016-12-28
EA035171B1 (ru) 2020-05-08
EP3533473A2 (en) 2019-09-04
AU2021200067A1 (en) 2021-03-18
AU2021200067B2 (en) 2023-02-02
IL261259B (en) 2020-07-30
TW201609153A (zh) 2016-03-16
IL261259A (en) 2018-10-31
CA2930581A1 (en) 2015-05-21
AU2023202704A1 (en) 2023-05-18
EP3777898A3 (en) 2021-04-21
US20220125958A1 (en) 2022-04-28
MX2022014611A (es) 2023-01-11
JP2022023172A (ja) 2022-02-07
CN105849568A (zh) 2016-08-10
AU2014348601A1 (en) 2016-05-26
EP3533473A3 (en) 2019-12-18
TWI657827B (zh) 2019-05-01
CN108514646A (zh) 2018-09-11
EP3069147A1 (en) 2016-09-21
JP6464166B2 (ja) 2019-02-06
KR20160079887A (ko) 2016-07-06
EP3777898A2 (en) 2021-02-17
IL245612A0 (en) 2016-06-30
JP2020165975A (ja) 2020-10-08
SG10201803618RA (en) 2018-06-28
JP2019023232A (ja) 2019-02-14
JP2023107988A (ja) 2023-08-03
NZ719939A (en) 2022-03-25
CN105849568B (zh) 2018-05-04
BR112016010927A2 (pt) 2017-08-08
CN108514646B (zh) 2021-07-16

Similar Documents

Publication Publication Date Title
US20220125958A1 (en) Compounds for positron emission tomography
AU2019225154B2 (en) Chemical conjugates of evans blue derivatives and their use as radiotherapy and imaging agents for targeting prostate cancer
CA2484345C (en) Folate-targeted imaging agents
ES2914593T3 (es) Agentes de unión a PSMA y usos de los mismos
NZ719939B2 (en) Compounds for positron emission tomography
JP4801786B6 (ja) ビタミンを標的とした造影剤

Legal Events

Date Code Title Description
AS Assignment

Owner name: PURDUE RESEARCH FOUNDATION, INDIANA

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:LOW, PHILIP S.;CHEN, QINGSHOU;REEL/FRAME:045014/0768

Effective date: 20141211

AS Assignment

Owner name: ENDOCYTE, INC, INDIANA

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:LEAMON, CHRISTOPHER P;VLAHOV, IONTCHO;PARHAM, GARTH L;REEL/FRAME:045089/0503

Effective date: 20180227

STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION