WO2023057457A1 - Ligands de protéine d'activation des fibroblastes radiomarqués - Google Patents

Ligands de protéine d'activation des fibroblastes radiomarqués Download PDF

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WO2023057457A1
WO2023057457A1 PCT/EP2022/077598 EP2022077598W WO2023057457A1 WO 2023057457 A1 WO2023057457 A1 WO 2023057457A1 EP 2022077598 W EP2022077598 W EP 2022077598W WO 2023057457 A1 WO2023057457 A1 WO 2023057457A1
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cancer
independently
compound
alkylene
cooh
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Aureliano ZANA
Andrea Galbiati
Jacopo MILLUL
Ettore GILARDONI
Riccardo STUCCHI
Samuele CAZZAMALLI
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Philochem Ag
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Priority to AU2022358921A priority patent/AU2022358921A1/en
Publication of WO2023057457A1 publication Critical patent/WO2023057457A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • C07B59/002—Heterocyclic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/10—Spiro-condensed systems
    • 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
    • C07F1/00—Compounds containing elements of Groups 1 or 11 of the Periodic System
    • C07F1/005—Compounds containing elements of Groups 1 or 11 of the Periodic System without C-Metal linkages
    • 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 System
    • C07F5/003—Compounds containing elements of Groups 3 or 13 of the Periodic System without C-Metal linkages
    • 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 System
    • C07F5/06—Aluminium compounds
    • C07F5/069—Aluminium compounds without C-aluminium linkages
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/05—Isotopically modified compounds, e.g. labelled

Definitions

  • the present invention relates to ligands of Fibroblast Activation Protein (FAP) for the active delivery of radioactive payloads at the site of disease.
  • FAP Fibroblast Activation Protein
  • the present invention relates to the development of FAP ligands for the targeted delivery of radionuclides, such as 18 Fluorine, 68 Gallium, ⁇ Copper, 11 ’Indium, 177 Lutetium, and to diagnostic methods and/or methods for therapy or surgery in relation to a disease or disorder, such as cancer, inflammation or another disease characterized by overexpression of FAP.
  • FAP Fibroblast Activation Protein
  • Fibroblast activation protein is a membrane -bound gelatinase which promotes tumor growth and progression and is overexpressed in cancer-associated fibroblasts.
  • FAP represents an ideal target for the development of targeted small molecule drug conjugates (SMDCs) and small molecule radio conjugates (SMRCs) due to its low expression in normal organs.
  • SMDCs small molecule drug conjugates
  • SMRCs small molecule radio conjugates
  • WO2019154886 and WO2019154859 describe heterocyclic compounds as fibroblast activation proteinalpha inhibitors used to treat different cancer types.
  • WO2019118932 describes substituted N-containing cyclic compounds as fibroblast activation protein alpha inhibitors used to treat different pathological conditions.
  • W02019083990 describes imaging and radiotherapeutic targeting fibroblast-activation protein-alpha (FAP-alpha) compounds as FAP-alpha inhibitors used for imaging disease associated with FAP-alpha and to treat proliferative diseases.
  • FAP-alpha fibroblast-activation protein-alpha
  • W02013107820 describes substituted pyrrolidine derivatives used in the treatment of proliferative disorders such as cancers and diseases indicated by tissue remodeling or chronic inflammation such as osteoarthritis, and notes that the 4-isoquinolinoyl and 8-quinolinoyl derivatives described therein are characterized by very low FAP-affinity.
  • W02005087235 describes pyrrolidine derivatives as dipeptidyl peptidase IV inhibitors to treat Type II diabetes.
  • WO2018111989 describes conjugates comprising fibroblast activation protein (FAP) inhibitor, bivalent linker and e.g. near infrared (NIR) dye, useful for removing cancer-associated fibroblasts, imaging population of cells in vitro, and treating cancer.
  • FAP fibroblast activation protein
  • NIR near infrared
  • Jansen et al. Med Chem Commun 2014
  • Jansen et al. J Med Chem 2014
  • Jansen et al. J Med Chem 2014
  • Mahetta et al. (Molecules 2015) describe the use of a boronic-acid based FAP inhibitor as non-invasive imaging tracers of atherosclerotic plaques. Dvofakova et al.
  • the present invention aims at the problem of providing improved compounds for targeted delivery, in particular SMRCs, which bind the fibroblast activation protein (FAP).
  • FAP fibroblast activation protein
  • the compounds (“binders”) should be suitable for therapeutic and/or diagnostic applications, and be capable of reaching a site afflicted by or at risk of disease or disorder characterized by overexpression of FAP.
  • the compound should form a stable complex with FAP, display a prolonged residence at the site of disease, and a lower accumulation in healthy organs.
  • the present inventors have found novel compounds (in particular: SMRCs) binding fibroblast activation protein (FAP) which are particularly suitable for targeting applications, and are suitable for addressing the above -described problems.
  • SMRCs binding fibroblast activation protein
  • FAP fibroblast activation protein
  • the present invention provides a compound, its individual diastereoisomers, its hydrates, its solvates, its crystal forms, its individual tautomers, or a pharmaceutically acceptable salt thereof, wherein the compound structure comprises: a moiety A represented by or comprising the following structure: one or more diagnostic or therapeutic agent moieties C; and a moiety B covalently connecting A to C, and comprising a carbocyclic or heterocyclic group.
  • the present invention further provides a pharmaceutical composition comprising said compound and a pharmaceutically acceptable excipient.
  • the present invention further provides said compound or pharmaceutical composition for use in a method for treatment of the human or animal body by surgery or therapy or a diagnostic method practiced on the human or animal body; as well as a method for treatment of the human or animal body by surgery or therapy or a diagnostic method practiced on the human or animal body comprising administering a therapeutically or diagnostically effective amount of said compound or pharmaceutical composition to a subject in need thereof.
  • the present invention further provides said compound or pharmaceutical composition for use in a method for therapy or prophylaxis of a subject suffering from or having risk for a disease or disorder; as well as a method for treatment therapy or prophylaxis of a disease or disorder comprising administering a therapeutically or diagnostically effective amount of said compound or pharmaceutical composition to a subject suffering from or having risk for said disease or disorder.
  • the present invention further provides said compound or pharmaceutical composition for use in a method for guided surgery practiced on a subject suffering from or having risk for a disease or disorder; as well as a method for guided surgery comprising administering a therapeutically or diagnostically effective amount of said compound or pharmaceutical composition to a subject suffering from or having risk for a disease or disorder.
  • the present invention further provides said compound or pharmaceutical composition for use in a method for diagnosis of a disease or disorder, the method being practiced on the human or animal body and involving a nuclear medicine imaging technique, such as Positron Emission Tomography (PET); as well as a method for diagnosis of a disease or disorder, the method being practiced on the human or animal body and involving a nuclear medicine imaging technique, such as Positron Emission Tomography (PET), and comprising administering a therapeutically or diagnostically effective amount of said compound or pharmaceutical composition to a subject in need thereof.
  • a nuclear medicine imaging technique such as Positron Emission Tomography (PET)
  • PET Positron Emission Tomography
  • the present invention further provides said compound or pharmaceutical composition for use in a method for targeted delivery of a therapeutic or diagnostic agent to a subject suffering from or having risk for a disease or disorder; as well as a method for targeted delivery of a therapeutically or diagnostically effective amount of said compound or pharmaceutical composition to a subject suffering from or having risk for a disease or disorder.
  • the aforementioned disease or disorder is characterized by overexpression of FAP and is independently selected from cancer, inflammation, atherosclerosis, fibrosis, tissue remodeling and keloid disorder, preferably wherein the cancer is selected from the group consisting of breast cancer, pancreatic cancer, small intestine cancer, colon cancer, multi-drug resistant colon cancer, rectal cancer, colorectal cancer, metastatic colorectal cancer, lung cancer, non-small cell lung cancer, head and neck cancer, ovarian cancer, hepatocellular cancer, esophageal cancer, hypopharynx cancer, nasopharynx cancer, larynx cancer, myeloma cells, bladder cancer, cholangiocarcinoma, clear cell renal carcinoma, neuroendocrine tumor, oncogenic osteomalacia, sarcoma, CUP (carcinoma of unknown primary), thymus cancer, desmoid tumors, glioma, astrocytoma, cervix cancer, skin cancer, kidney cancer,
  • ESV6-NODAGA-A1-F Chromatographic purity of the labelling procedure measured by LC- UV-MS (Agilent 6100 Series Single Quadrupole MS System combined with Agilent 1200 Series LC System. Chromatographic method Water/ACN + 0.1% HCOOH 90:10 to 0:100 in 3 min) identified a single chemical species after labelling.
  • ESV6-NOTA (Compound 1): Chromatographic purity of the labelling procedure measured by LC-UV-MS (Agilent 6100 Series Single Quadrupole MS System combined with Agilent 1200 Series LC System. Chromatographic method Water/ACN + 0.1% HCOOH 90:10 to 0:100 in 3 min) identified a single chemical species after labelling.
  • FIG. 1 Schematic workflow of the ex-vivo biodistribution experiments: Mice were treated with either ESV6-NODAGA-A1-F (represented as a sum of the three species) or ESV6-NOTA-A1-F (Compound A1F@1) and euthanized after two hours. Tissues were harvested, deproteinized, cleaned up with two SPE in line, and analyzed with a nanoLC-HR-MS platform. As internal standard for the MS analysis, isotopically labelled derivative of the analytes at fixed concentrations were added to the samples prior to sample preparation.
  • ESV6-NODAGA-A1-F represented as a sum of the three species
  • ESV6-NOTA-A1-F Compound A1F@1
  • FIG. 7 Quantitative in vivo biodistribution results of ESV6-NOTA-[ 18 F]A1-F in nude mice bearing subcutaneous HT-1080.hFAP tumors: results are expressed as the percentage of injected dose per gram of tissue (A) and as tumor to organs ratio (B). The preferential uptake of ESV6-NOTA-[ 18 F]A1-F is remarkable while the uptake in normal organs is at negligible levels.
  • the present inventors have identified compounds, and in particular small molecule radio conjugates (SMRCs), which bind to the fibroblast activation protein (FAP), and are suitable for targeting applications.
  • SMRCs small molecule radio conjugates
  • FAP fibroblast activation protein
  • the SMRCs according to the invention provide good inhibition of FAP, good affinity for FAP and/or are suitable for targeted delivery of a payload, such as a therapeutic or diagnostic agent, to a site afflicted by or at risk of disease or disorder characterized by overexpression of FAP.
  • the compounds according to the present invention form a stable complex with FAP, display an increased affinity, increased inhibitory activity, a slower rate of dissociation from the complex, and/or prolonged residence at a disease site.
  • the compounds according to the invention further can have an increased tumor-to-liver, tumor-to-kidney and/or tumor-to-intestine uptake ratio; a more potent anti-tumor effect (e.g., measured by mean tumor volume increase), and/or lower toxicity (e.g., as assessed by the evaluation of changes (%) in body weight).
  • the compounds according to the invention preferably attain FAP-specific cellular binding; FAP-selective accumulation on the cell membrane; FAP-selective accumulation inside the cytosol.
  • the compounds according to the invention preferably can rapidly and homogeneously localize at the tumor site in vivo with a high tumor-to-organs selectivity, in particular for melanoma and/or renal cell carcinoma.
  • Compounds according to the invention comprising a radioactive payload e.g., 18 Fluorine
  • a radioactive payload e.g. 18 Fluorine
  • target saturation reached between 500 pmol/g and 1000 pmol/g reached and/or maintained at up to 12 h, more preferably 1 to 9 h, further more preferably 1 to 3 h after intravenous administration.
  • PET imaging is one of the preferred applications of the compounds described herein.
  • Affinity for FAP, lipophilicity and stability of the compounds can be among the relevant factors determining the suitability of a SMRC for such applications.
  • PET and gamma counting-based biodistribution can be used to assess tracer kinetics and uptake.
  • the compounds described herein are believed to exhibit favourable biodistribution and kinetics with high and reliable uptake in cancer tissues, which is believed to result from the combination of the moiety A with a very high FAP binding affinity, the particular linking group B, and a radioactive therapeutic or diagnostic moiety C.
  • the present invention provides a compound, its individual diastereoisomers, its hydrates, its solvates, its crystal forms, its individual tautomers, or a pharmaceutically acceptable salt thereof, wherein the compound structure comprises a moiety A represented by or comprising the following structure:
  • A is a binding moiety (i.e., moiety binding to FAP), and is covalently connected to one or more one or more diagnostic or therapeutic agent moieties C (i.e., payload(s), such as a radioactive group comprising a radionuclide) through a moiety B.
  • diagnostic or therapeutic agent moieties C i.e., payload(s), such as a radioactive group comprising a radionuclide
  • each B can be represented by the following structure: wherein each b 1 and b 3 is independently an integer from 0 to 4, preferably 0 or 1; each b 2 is independently an integer from 1 to 4, preferably 1 or 2; z is an integer from 1 to 3, preferably 1 or 2; each B 2 is independently represented by wherein:
  • Y and Z are linking groups forming part of a carbocyclic or heterocyclic group, preferably a C3-13 carbocyclic or C2 12 heterocyclic group, wherein all valences are satisfied.
  • *-Y preferably represents *-C, *-CR, *-N, *-NR, *-NRC(O)C, *-NRC(O)CR,
  • Z— preferably represents C— , CR— , N— , NR—, CC(O)NRCRC(O)NR— , CCR 2 C(O)NR— , CRCR 2 C(O)NR-, CNRC(S)NR-, NRC(S)CRNR-, CNR-, CRNR-, CCR2NR-, or CRCR2NR— ;
  • Each * represents a point of attachment closer to moiety A than to a moiety C; and each • represents a point of attachment closer to a moiety C than to moiety A.
  • Each B 3 is independently a bond, alkylene, oxoalkylene, di(oxo)alkylene, C(O)alkylarylalkylene, C(S)N(R)arylalkylene, or heteroalkylene, said heteroalkylene comprising one or more heteroatoms selected from N and O; and is preferably a bond, alkylene, oxoalkylene, di(oxo)alkylene, C(O)alkylarylalkylene, or C(S)N(R)arylalkylene.
  • the shortest path between B 2 and C preferably comprises 10 or less, more preferably 7 or less, most preferably 6 or less covalently connected atoms or is a bond.
  • Each of B 1 , B 2 and B 3 independently optionally substituted by one or more of R.
  • Each R is independently selected from H, OH, SH, NH 2 , halogen, cyano, oxo, carboxy, C(O)NH 2 C 1–6 alkyl, C 1–6 alkoxy, C(O)C 1–6 alkyl, C 1–6 alkylthio, C 1–5 heteroalkyl, C 1–5 heteroalkoxy, C 3–6 cycloalkyl, C 3– 6 cycloalkoxy, C 6–10 aryl, C 6–10 aryloxy, C 5–10 heteroaryl and C 5–10 heteroaryloxy, of which the SH, NH 2 , C(O)NH 2 , C 1–6 alkyl, C 1–6 alkoxy, C(O)C 1–6 alkyl, C 1–6 alkylthio, C 1–5 heteroalkyl, C 1–5 heteroalkoxy, C 3–6 cycloalkyl, C 3–6 cycloalkoxy, C 6–10 ary
  • a compound according to the present invention may be represented by Formula I: Therein, B is a covalent bond or a moiety comprising a chain of atoms covalently attaching A to C.
  • C is a therapeutic or diagnostic agent, which may be, e.g., an atom, a molecule, a particle, or a radionuclide.
  • Moiety A Without wishing to be bound by any theory, it is contemplated that some of the beneficial technical effects achieved by the compounds of the invention are associated with the particular structure of the binding moiety A wherein the quinoline ring is substituted at the 8-position by a nitrogen-containing group, such as an amino or amido group:
  • the compounds of the present invention have an increased affinity, slower dissociation rate with respect to FAP as compared to prior art compounds, and therefore are also considered to as having a prolonged residence at the disease site at a therapeutically or diagnostically relevant level, preferably beyond 1 h, more preferably beyond 6 h post injection.
  • the highest enrichment is achieved after 5 min, 10 min, 20 min, 30 min, 45 min, 1 h, 2 h, 3 h, 4 h, 5 h or 6 h; and/or enrichment in the disease site is maintained at a therapeutically or diagnostically relevant level, over a period of or at least for 5 min, 10 min, 20 min, 30 min, 45 min, 1 h, 2 h, 3 h, 4 h, 5 h or 6 h, more preferably beyond 6 h post injection.
  • Compounds according to the invention comprising a radioactive payload may attain dose-dependent response, e.g., with target saturation reached between 500 pmol/g and 1000 pmol/g reached and/or maintained at up to 12 h, more preferably 1 to 9 h, further more preferably 1 to 3 h after intravenous administration.
  • a radioactive payload e.g. 18 Fluorine
  • target saturation reached between 500 pmol/g and 1000 pmol/g reached and/or maintained at up to 12 h, more preferably 1 to 9 h, further more preferably 1 to 3 h after intravenous administration.
  • the binding moiety A has the following structure A 1 , A 2 or A 3 , wherein m is 0, 1, 2, 3, 4, or 5, preferably 1; and n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, preferably 2:
  • moiety A has the structure A 2 , most preferably wherein m is 1.
  • Moiety B is a covalent bond or a moiety comprising a chain of atoms that covalently attaches A to the payload(s) C, i.e., through one or more covalent bond(s).
  • the moiety B links one or more payload and/or binder moieties to form the targeted conjugate of the invention.
  • the structure of the compound comprises one moiety A and more than one moieties C per molecule, e.g., 2, 3, 4, 5, 6, 7, 8, 9 or 10 moieties C per molecule.
  • one moiety C can be attached to moiety B at the position indicated by • in any of the general formulae disclosed herein, and the remaining moieties C are attached as substituents at further positions on moiety B.
  • Moiety B can be represented by the following structure: wherein each b 1 and b 3 is independently an integer from 0 to 4, preferably 0 or 1; each b 2 is independently an integer from 1 to 4, preferably 1 or 2; z is an integer from 1 to 3, preferably 1 or 2; each B 2 is independently represented by wherein Y and Z are linking groups forming part of a carbocyclic or heterocyclic group; each * represents a point of attachment closer to moiety A than to a moiety C; each • represents a point of attachment closer to a moiety C than to moiety A; each B 1 is independently a bond, alkylene, oxoalkylene, di(oxo)alkylene, C(O)alkylarylalkylene, C(S)N(R)arylalkylene, or heteroalkylene, said heteroalkylene comprising one or more heteroatoms selected from N and O; each B 3 is independently a bond, alkylene, oxoalkylene, di(oxo)al
  • * represents a point of attachment to moiety A or a point of attachment for which the shortest path to moiety A comprises less atoms than that for •, as the case may be; and • represents a point of attachment a point of attachment to moiety C or a point of attachment to moiety C for which the shortest path to moiety C comprises less atoms than that for *, as the case may be.
  • Each B 1 is independently a bond, alkylene, oxoalkylene, di(oxo)alkylene, C(O)alkylarylalkylene, C(S)N(R)arylalkylene, or heteroalkylene, said heteroalkylene comprising one or more heteroatoms selected from N and O; and is preferably a bond, alkylene or heteroalkylene, said heteroalkylene comprising one or more heteroatoms selected from N and O.
  • the shortest path between A and B 2 preferably comprises 6 or less, more preferably 3 or less, most preferably 2 or less covalently connected atoms or is a bond.
  • b 1 is 0 or 1; b 2 is 1; b 3 is 1; and z is 1.
  • B 1 is a bond, alkylene or heteroalkylene, said heteroalkylene comprising one or more heteroatoms selected from N and O.
  • the shortest path between A and B 2 preferably comprises 6 or less, more preferably 3 or less, most preferably 2 or less covalently connected atoms or is a bond.
  • B 3 a bond, alkylene, oxoalkylene, di(oxo)alkylene, C(O)alkylarylalkylene, or C(S)N(R)arylalkylene; wherein the shortest path between B 2 and C preferably comprises 10 or less, more preferably 7 or less, most preferably 6 or less covalently connected atoms or is a bond.
  • the shortest path between B 2 and C preferably comprises 10 or less, more preferably 7 or less, most preferably 6 or less covalently connected atoms or is a bond.
  • * –Y represents * –C, * –CR, * –N, * –NR, * –NRC(O)C, * –NRC(O)CR, * –NRC(O)CR 2 C, * –NRC(O)CR 2 CR, * –NRC(S)NRC, * –NRC(S)NRCR, * –NRC, * –NRCR, * –NRCR 2 C, or * –NRCR 2 CR; and Z– • represents C– • , CR– • , N– • , NR– • , CC(O)NRCRC(O)NR– • , CCR 2 C(O)NR– • , CRCR 2 C(O)NR– • , CNRC(S)NR– • , NRC(S)CRNR– • , CNR– • , CRNR– • , CCR 2 NR– • , or CRCR 2 NR– • .
  • each B 1 is independently selected from bond; C 1–10 , preferably C 1–4 , more preferably C 1–2 alkylene; C 1–10 , preferably C 1–4, more preferably C 1–2 heteroalkylene group comprising one or two N atoms; NR(C 1–10 , C 1–4 , or C 1–2 alkylene)NR; (C 1–10 , C 1–4 , or C 1–2 alkylene)NR; NR(C 1–10 , C 1–4 , or C 1–2 alkylene); C(O); C(O)CR 2 ; C(O)(C 6–10 aryl)CR 2 ; C(O)(C 1–10 alkylene)C(O); C(O)(C 1–10 alkyl)C(O)NR; C(O)(C 5–10 heteroaryl)CR 2 ; C(O)(C 6–10 aryl)CR 2 ; C(O)(C 5–10 heteroaryl)
  • B 1 is bond, C(O)CH 2 CH 2 C(O), NHCH 2 CH 2 NH, CH 2 CH 2 NH, NHCH 2 CH 2 , most preferably bond or NHCH2CH2NH.
  • each B 3 is independently selected from bond; C 1–10 , preferably C 1–4, more preferably C1–2 alkylene; C1–10, preferably C1–4, more preferably C1–2 heteroalkylene group comprising one or two N atoms; NR(C 1–10 , C 1–4 , or C 1–2 alkylene)NR; (C 1–10 , C 1–4 , or C 1–2 alkylene)NR; NR(C 1–10 , C 1–4 , or C 1–2 alkylene); C(O); C(O)CR 2 ; C(O)(C 6–10 aryl)CR 2 ; C(O)(C 5–10 heteroaryl)CR 2 ; C(O)(C
  • B 3 is bond, C(O)CH 2 CH 2 C(O), NHCH 2 CH 2 NH, CH 2 CH 2 NH, NHCH 2 CH 2,
  • moiety A has the structure A 2 ; m is 1; b 1 is 0 or 1; b 2 is 1; b 3 is 1; and z is 1; and each of s, u, t, and v, if present, is 1, and w is 0 or 1.
  • B 2 is independently selected from: wherein each s, u, t, and v is independently 0, 1, or 2; each w is independently 0, 1, 2, or 3; and each X is independently N, NH, NR, S, S(O), SO2, O, C, CR, CH, CR2 or CH2; preferably N.
  • each of s, u, t, and v, if present, is 1, and w is 0 or 1.
  • B 2 is selected from: In a more preferred embodiment, B 2 is selected from:
  • B 2 is selected from:
  • B 2 is most preferably
  • B 2 is B 2 is ; more preferably most preferably
  • Moiety B preferably comprises, more preferably consists of a unit from the following list:
  • Moiety C in the present invention represents a pay load, which can be generally any atom (including H), molecule or particle, and can function as a therapeutic or diagnostic agent.
  • moiety C is not a hydrogen atom, and may be selected from: a chelating agent group suitable for radiolabelling; a radioactive group comprising a radioisotope; a chelate of a radioactive isotope with a chelating agent; a fluorophore group; a cytotoxic and/or cytostatic agent; immunomodulator agent; or a protein
  • Payload moiety C may comprise of consist of a chelating agent (chelator) for radiolabeling.
  • Payload moiety C may be a radioactive group comprising or consisting of radioisotope including isotopes such as 223 Ra, 89 Sr, 94m Tc, " m Tc, 186 Re, 188 Re, 203 Pb, 66 Ga 67 Ga, 68 Ga, 43 Sc, ⁇ Sc 47 Sc, 11 ‘in, 97 Ru, 62 Cu, M Cu. 86 Y , 88 Y, 90 Y, 121 Sn, 161 Tb, 153 Sm, 166 Ho, 105 Rh, 177 Lu, 123 I, 124 I, 125 I, 131 I, 18 F, 211 At, 225 Ac, 89 Sr, 117m Sn and 169 E.
  • the radioisotopes are 68 Ga 62 Cu, M Cu, 1 H In, 18 F.
  • 18 F is bound to a cation; more preferably, the cation is aluminium (Al) in any of its oxidation states.
  • the payload may be a chelate of an isotope, preferably of a radioactive isotope, listed under above.
  • the chelating agent group suitable for radiolabelling may be derived from 1,4,7-triazacyclononane- N,N',N"-triacetic acid (NOTA), 2,2',2"-(l,4,7-triazonane-l,4-diyl)diacetic acid (NODA), 2,2'-((2-((4-(2- amino-2-oxoethyl)benzyl)(carboxymethyl)amino)cyclohexyl)azanediyl)diacetic acid] (RESCA), sulfur colloid, diethylenetriaminepentaacetic acid (DTP A), ethylenediaminetetraacetic acid (EDTA), 1,4,7,10- tetraazacyclododecane-N,N',N",N"'-tetraacetic acid (DOT A), [2,2',2"-(10-(4-((2-aminoethyl)amino)-l- carboxy-4
  • the chelating agent group may have a structure according to one of the following formulae C 1 , C 2 , C 3 , C 4 , and C 5 : wherein: each q is independently 0, 1, 2, 3, 4 or 5; preferably 0; R 1e , R 1f , R 1g , R 1h , and R 1i are each independently H, COOH, aryl-COOH or heteroaryl-COOH; preferably COOH; R 2e, R 2f , R 2g , R 2h , and R 2i are each independently H, COOH, aryl-COOH or heteroaryl-COOH; preferably COOH; R 3e, R 3f , R 3g , R 3h , R 4h , and R 3i are each independently H, COOH, aryl-COOH or heteroaryl-COOH; preferably COOH; and and R 4e is independently H, COOH, aryl-COOH or heteroaryl-COOH, with the proviso that when q is 0,
  • the chelating agent group may have a structure selected from the following:
  • the radioactive group in general, may comprise a radioisotope is selected from 223 Ra, 89 Sr, 94m Tc, 99m Tc, 1 86 Re, 188 Re, 203 Pb, 67 Ga, 68 Ga, 47 Sc, 111 In, 97 Ru, 62 Cu, 64 Cu, 86 Y, 88 Y, 90 Y, 121 Sn, 161 Tb, 153 Sm, 166 Ho, 105 Rh, 1 77 Lu, 123 I, 124 I, 125 I, 131 I, 18 F, 211 At, 225 Ac, 89 Sr, 117m Sn and 169 Er.
  • radioactive groups useful in the present invention e.g., chelate complexes with one or more of the chelators described herein, 18 F, when present, is preferably bound to chelated Al, Zr, Si, Ga, or In, more preferably 18 F is bound to Al chelated by the chelator.
  • 18 F is bound to Al chelated by the chelator.
  • also complexes of the chelators described herein are contemplated wherein F is present, which is preferably bound to chelated Al, Zr, Si, Ga, or In, wherein F can contain any isotope of fluorine, e.g., 18 F and/or 19 F.
  • diagnostic or therapeutic agents C for use in the present invention are chelates of a radioactive isotope listed under above with any of the chelating agents listed under (a) above.
  • diagnostic or therapeutic agents C is a group selected from any of the following structures comprising covalently bound radioactive nuclides: wherein X is as defined further above, and can be, e.g., N, S, S(O), SO 2 , O, CR, CH; preferably CH or N.
  • a preferred structure comprising covalently a bound radioactive nuclide is
  • compounds are also contemplated wherein any isotope of F or I can be present instead of 18 F, 123 I, 124 I, 125 I or 131 I, as the case may be.
  • moiety C is a chelator selected from:
  • chelators are derived from derived from:
  • these chelators and their Al-F complexes are particularly advantageous from the viewpoint of activity labelling, stability, especially with respect to chemical and radiolytic stability and stability.
  • Preferred compounds are listed in the appended claims, especially claim 14, as well as chelate complexes of thereof with ions or radionuclides as listed above, such as A1F (containing, e.g., 18 F and/or 19 F bound to
  • A1F complex A1F@1 which can contain 18 F and/or 19 F, even more preferably 18 F, bound to Al.
  • moiety C can be a fluorophore group.
  • the fluorophore group is selected from a xanthene dye, acridine dye, oxazine dye, cyanine dye, styryl dye, coumarine dye, porphine dye, fluorescent metal-ligand-complex, fluorescent protein, nanocrystals, perylene dye, boron-dipyrromethene dye and phtalocyanine dye.
  • Preferred structures may be selected from the following:
  • moiety C can be a cytotoxic and/or cytostatic agent, e.g., a chemotherapeutic agent.
  • cytotoxic and/or cytostatic agent e.g., a chemotherapeutic agent.
  • therapeutic agents are selected from the group consisting of topoisomerase inhibitors, alkylating agents, antimetabolites, antibiotics, mitotic disrupters, DNA intercalating agents, DNA synthesis inhibitors, DNA-RNA transcription regulator, enzyme inhibitors, gene regulators, hormone response modifiers, hypoxia-selective cytotoxins, epidermal growth factor inhibitors, anti-vascular agents and a combination of two or more thereof.
  • Such agents can inhibit or prevent the function of cells and/or cause destruction of cells.
  • cytotoxic agents include radioactive isotopes, chemotherapeutic agents, and toxins such as small molecule toxins or enzymatically active toxins of bacterial, fungal, plant or animal origin, including synthetic analogues and derivatives thereof.
  • the cytotoxic agent may be selected from the group consisting of an auristatin, a DNA minor groove binding agent, a DNA minor groove alkylating agent, an enediyne, a lexitropsin, a duocarmycin, a taxane, a puromycin, a dolastatin, a maytansinoid and a vinca alkaloid or a combination of two or more thereof.
  • Preferred cytotoxic and/or cytostatic payload moieties are listed in claim 8 (e).
  • the payload is a chemotherapeutic agent selected from the group consisting of a topoisomerase inhibitor, an alkylating agent (e.g., nitrogen mustards; ethylenimes; alkylsulfonates; triazenes; piperazines; and nitrosureas), an antimetabolite (e.g., mercaptopurine, thioguanine, 5- fluorouracil), an antibiotics (e.g., anthracyclines, dactinomycin, bleomycin, adriamycin, mithramycin.
  • a chemotherapeutic agent selected from the group consisting of a topoisomerase inhibitor, an alkylating agent (e.g., nitrogen mustards; ethylenimes; alkylsulfonates; triazenes; piperazines; and nitrosureas), an antimetabolite (e.g., mercaptopurine, thioguanine, 5- fluor
  • dactinomycin a mitotic disrupter (e.g., plant alkaloids - such as vincristine and/or microtubule antagonists - such as paclitaxel), a DNA methylating agent, a DNA intercalating agent (e.g., carboplatin and/or cisplatin, daunomycin and/or doxorubicin and/or bleomycin and/or thalidomide), a DNA synthesis inhibitor, a DNA-RNA transcription regulator, an enzyme inhibitor, a gene regulator, a hormone response modifier, a hypoxia-selective cytotoxin (e.g., tirapazamine), an epidermal growth factor inhibitor, an anti- vascular agent (e.g., xanthenone 5,6-dimethylxanthenone-4-acetic acid), a radiation-activated prodrug (e.g., nitroarylmethyl quaternary (NMQ) salts) or a bioreductive drug or a combination of two or more
  • the chemotherapeutic agent may selected from the group consisting of Erlotinib (TARCEVA®), Bortezomib (VELCADE®), Fulvestrant (FASLODEX®), Sutent (SU11248), Letrozole (FEMARA®), Imatinib mesylate (GLEEVEC®), PTK787/ZK 222584, Oxaliplatin (Eloxatin®.), 5-FU (5 -fluorouracil), Leucovorin, Rapamycin (Sirolimus, RAPAMUNE®.), Lapatinib (GSK572016), Lonafarnib (SCH 66336), Sorafenib (BAY43-9006), and Gefitinib (IRESSA®.), AG1478, AG1571 (SU 5271; Sugen) or a combination of two or more thereof.
  • TARCEVA® Erlotinib
  • VELCADE® Bortezomib
  • FASLODEX® Fulvestrant
  • the chemotherapeutic agent may be an alkylating agent - such as thiotepa, CYTOXAN® and/or cyclosphosphamide; an alkyl sulfonate - such as busulfan, improsulfan and/or piposulfan; an aziridine - such as benzodopa, carboquone, meturedopa and/or uredopa; ethylenimines and/or methylamelamines - such as altretamine, triethylenemelamine, triethylenepbosphor amide, triethylenethiophosphoramide and/or trimethylomelamine; acetogenin - such as bullatacin and/or bullatacinone; camptothecin; bryostatin; callystatin; cryptophycins; dolastatin; duocarmycin; eleutherobin; pancratistatin; sarcodictyin; spongistatin; nitrogen mustard
  • doxorubicin - such as morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and/or deoxydoxorubicin, epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins - such as mitomycin C, mycophenolic acid, nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; antimetabolites - such as methotrexate and 5 -fluorouracil (5-FU); folic acid analogues - such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogues - such as fludarabine, 6-mercaptopurine, thiamiprine
  • paclitaxel paclitaxel, abraxane, and/or TAXOTERE®, doxetaxel; chlor anbucil; GEMZAR®.
  • gemcitabine 6-thioguanine; mercaptopurine; methotrexate; platinum analogues - such as cisplatin and carboplatin; vinblastine; platinum; etoposide; ifosfamide; mitoxantrone; vincristine; NAVELBINE®, vinorelbine; novantrone; teniposide; edatrexate; daunomycin; aminopterin; xeloda; ibandronate; topoisomerase inhibitor RFS 2000; difluoromethylomithine (DMFO); retinoids - such as retinoic acid; capecitabine; and pharmaceutically acceptable salts, acids, derivatives or combinations of two or more of any of the above.
  • DMFO difluoromethylomit
  • the pay load may be a tubulin disruptor including but are not limited to: taxanes - such as paclitaxel and docetaxel, vinca alkaloids, discodermolide, epothilones A and B, desoxyepothilone, cryptophycins, curacin A, combretastatin A-4-phosphate, BMS 247550, BMS 184476, BMS 188791; LEP, RPR 109881A, EPO 906, TXD 258, ZD 6126, vinflunine, LU 103793, dolastatin 10, E7010, T138067 and T900607, colchicine, phenstatin, chaicones, indanocine, T138067, oncocidin, vincristine, vinblastine, vinorelbine, vinflunine, halichondrin B, isohomohalichondrin B, ER-86526, pironetin, spongistatin 1, spiket P, cryptophyc
  • the payload may be a DNA intercalator including but are not limited to: acridines, actinomycins, anthracyclines, benzothiopyranoindazoles, pixantrone, crisnatol, brostallicin, CI-958, doxorubicin (adriamycin), actinomycin D, daunorubicin (daunomycin), bleomycin, idarubicin, mitoxantrone, cyclophosphamide, melphalan, mitomycin C, bizelesin, etoposide, mitoxantrone, SN-38, carboplatin, cisplatin, actinomycin D, amsacrine, DACA, pyrazoloacridine, irinotecan and topotecan and pharmaceutically acceptable salts, acids, derivatives or combinations of two or more of any of the above.
  • a DNA intercalator including but are not limited to: a
  • the payload may be an anti-hormonal agent that acts to regulate or inhibit hormone action on tumours - such as anti-estrogens and selective estrogen receptor modulators, including, but not limited to, tamoxifen, raloxifene, droloxifene, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, and/or fareston toremifene and pharmaceutically acceptable salts, acids, derivatives or combinations of two or more of any of the above.
  • an anti-hormonal agent that acts to regulate or inhibit hormone action on tumours -
  • selective estrogen receptor modulators including, but not limited to, tamoxifen, raloxifene, droloxifene, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, and/or fareston toremifene and pharmaceutically acceptable salts, acids, derivatives or combinations of two or more of
  • the payload may be an aromatase inhibitor that inhibits the enzyme aromatase, which regulates estrogen production in the adrenal glands - such as, for example, 4(5)-imidazoles, aminoglutethimide, megestrol acetate, AROMASIN®. exemestane, formestanie, fadrozole, RIVISOR®. vorozole, FEMARA®. letrozole, and ARIMIDEX® and/or anastrozole and pharmaceutically acceptable salts, acids, derivatives or combinations of two or more of any of the above.
  • an aromatase inhibitor that inhibits the enzyme aromatase, which regulates estrogen production in the adrenal glands - such as, for example, 4(5)-imidazoles, aminoglutethimide, megestrol acetate, AROMASIN®. exemestane, formestanie, fadrozole, RIVISOR®. vorozole, FEMARA®. letrozole, and ARIM
  • the payload may be an anti-androgen such as flutamide, nilutamide, bicalutamide, leuprolide, goserelin and/or troxacitabine and pharmaceutically acceptable salts, acids, derivatives or combinations of two or more of any of the above.
  • an anti-androgen such as flutamide, nilutamide, bicalutamide, leuprolide, goserelin and/or troxacitabine and pharmaceutically acceptable salts, acids, derivatives or combinations of two or more of any of the above.
  • moiety C is an auristatin (i.e., having a structure derived from an auristatin compound family member) or an auristatin derivative. More preferably, moiety C has a structure according to the following formula: wherein:
  • Rid is independently H or C
  • R ⁇ d is independently C
  • R ⁇ d is independently H or C
  • R4d is independently H, C 1 -C 6 alkyl, COO(C 1 -C 6 alkyl), CON(H or C 1 -C 6 alkyl), C 3 -C 10 aryl or C 3 - C 10 heteroaryl; preferably H, CH 3 , COOH, COOCH 3 or thiazolyl;
  • R 5d is independently H, OH, C 1 -C 6 alkyl; preferably H or OH; and
  • R6d is independently C 3 -C 1 0 aryl or C 3 -C 1 0 heteroaryl; preferably optionally substituted phenyl or pyridyl.
  • moiety C is selected from the following structures:
  • moiety C can be a immunomodulator agent.
  • the immunomodulator agent is preferably selected from molecules known to be able to modulate the immune system, such as ligands of CD3, CD25, TLRs, STING, 4-1BBL, 4-1BB, PD-1, mTor, PDL-1, NKG-2D IMiDs, wherein ligands can be agonists and/or antagonists.
  • moiety C can be a protein or an antibody.
  • the payload is a cytokine (e.g., an interleukin such as IL2, IL 10, IL 12, IL15; a member of the TNF superfamily; or an interferon such as interferon gamma.).
  • Any payload may be used in unmodified or modified form. Combinations of payloads in which some are unmodified and some are modified may be used.
  • the payload may be chemically modified.
  • One form of chemical modification is the derivatisation of a carbonyl group - such as an aldehyde.
  • the compounds described herein may be used to treat disease.
  • the treatment may be therapeutic and/or prophylactic treatment, with the aim being to prevent, reduce or stop an undesired physiological change or disorder.
  • the treatment may prolong survival as compared to expected survival if not receiving treatment.
  • the disease that is treated by the compound may be any disease that might benefit from treatment. This includes chronic and acute disorders or diseases including those pathological conditions which predispose to the disorder.
  • cancer and “cancerous” is used in its broadest sense as meaning the physiological condition in mammals that is typically characterized by unregulated cell growth.
  • a tumor comprises one or more cancerous cells.
  • the therapeutically effect that is observed may be a reduction in the number of cancer cells; a reduction in tumor size; inhibition or retardation of cancer cell infiltration into peripheral organs; inhibition of tumor growth; and/or relief of one or more of the symptoms associated with the cancer.
  • efficacy may be assessed by physical measurements of the tumor during the treatment, and/or by determining partial and complete remission of the cancer.
  • efficacy can, for example, be measured by assessing the time to disease progression (TTP) and/or determining the response rate (RR).
  • methods for treatment e.g., by therapy or prophylaxis, of a subject suffering from or having risk for a disease or disorder; or by guided surgery practiced on a subject suffering from or having risk for a disease or disorder; method for diagnosis of a disease or disorder, e.g., diagnostic method practiced on the human or animal body and/or involving a nuclear medicine imaging technique, such as Positron Emission Tomography (PET) or Single Photon Emission Computed Tomography (SPECT); method for targeted delivery of a therapeutic or diagnostic agent to a subject suffering from or having risk for a disease or disorder.
  • PET Positron Emission Tomography
  • SPECT Single Photon Emission Computed Tomography
  • said disease or disorder may be independently selected from cancer, inflammation, atherosclerosis, fibrosis, tissue remodeling and keloid disorder, preferably wherein the cancer is selected from the group consisting of breast cancer, pancreatic cancer, small intestine cancer, colon cancer, multi-drug resistant colon cancer, rectal cancer, colorectal cancer, metastatic colorectal cancer, lung cancer, non-small cell lung cancer, head and neck cancer, ovarian cancer, hepatocellular cancer, esophageal cancer, hypopharynx cancer, nasopharynx cancer, larynx cancer, myeloma cells, bladder cancer, cholangiocarcinoma, clear cell renal carcinoma, neuroendocrine tumor, oncogenic osteomalacia, sarcoma, CUP (carcinoma of unknown primary), thymus cancer, desmoid tumors, glioma, astrocytoma, cervix cancer, skin cancer, kidney cancer and prostate cancer.
  • the cancer is selected from the group consisting of
  • a pharmaceutical composition comprising the compound according to any of the preceding aspects, and a pharmaceutically acceptable excipient.
  • Such pharmaceutical composition is also disclosed for use in: (a) a method for treatment of the human or animal body by surgery or therapy or a diagnostic method practiced on the human or animal body; or (b) a method for therapy or prophylaxis of a subject suffering from or having risk for a disease or disorder; or (c) a method for guided surgery practiced on a subject suffering from or having risk for a disease or disorder; or (d) a method for diagnosis of a disease or disorder, the method being practiced on the human or animal body and involving a nuclear medicine imaging technique, such as Positron Emission Tomography (PET) or Single Photon Emission Computed Tomography (SPECT); or (e) a method for targeted delivery of a therapeutic or diagnostic agent to a subject suffering from or having risk for a disease or disorder, wherein in each of the preceding (b)-(e), said disease or disorder is independently selected from cancer, inflammation
  • the compounds described herein may be in the form of pharmaceutical compositions which may be for human or animal usage in human and veterinary medicine and will typically comprise any one or more of a pharmaceutically acceptable diluent, carrier, or excipient.
  • Acceptable carriers or diluents for therapeutic use are well known in the pharmaceutical art, and are described, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co. (A. R. Gennaro edit. 1985).
  • the choice of pharmaceutical carrier, excipient or diluent can be selected with regard to the intended route of administration and standard pharmaceutical practice.
  • the pharmaceutical compositions may comprise as - or in addition to - the carrier, excipient or diluent any suitable binder(s), lubricant(s), suspending agent(s), coating agent(s), solubilizing agent(s).
  • Preservatives, stabilizers, dyes and even flavoring agents may be provided in the pharmaceutical composition.
  • preservatives include sodium benzoate, sorbic acid and esters of p- hydroxybenzoic acid.
  • Antioxidants and suspending agents may be also used.
  • the pharmaceutical composition may be formulated to be administered using a mini-pump or by a mucosal route, for example, as a nasal spray or aerosol for inhalation or ingestable solution, or parenterally in which the composition is formulated by an injectable form, for delivery, by, for example, an intravenous, intramuscular or subcutaneous route.
  • the formulation may be designed to be administered by a number of routes.
  • the agent If the agent is to be administered mucosally through the gastrointestinal mucosa, it should be able to remain stable during transit though the gastrointestinal tract; for example, it should be resistant to proteolytic degradation, stable at acid pH and resistant to the detergent effects of bile.
  • the pharmaceutical compositions may be administered by inhalation, in the form of a suppository or pessary, topically in the form of a lotion, solution, cream, ointment or dusting powder, by use of a skin patch, orally in the form of tablets containing excipients such as starch or lactose, or in capsules or ovules either alone or in admixture with excipients, or in the form of elixirs, solutions or suspensions containing flavoring or coloring agents, or the pharmaceutical compositions can be injected parenterally, for example, intravenously, intramuscularly or subcutaneously.
  • compositions may be best used in the form of a sterile aqueous solution which may contain other substances, for example, enough salts or monosaccharides to make the solution isotonic with blood.
  • compositions may be administered in the form of tablets or lozenges which can be formulated in a conventional manner.
  • the compound of the present invention may be administered in the form of a pharmaceutically acceptable or active salt.
  • Pharmaceutically-acceptable salts are well known to those skilled in the art, and for example, include those mentioned by Berge et al, in J.Pharm.Sci., 66, 1-19 (1977).
  • Salts include, but are not limited, to sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)) salts.
  • pamoate i.e., 1,1'-methylene-bis-(2-hydroxy-3-
  • the routes for administration may include, but are not limited to, one or more of oral (e.g. as a tablet, capsule, or as an ingestable solution), topical, mucosal (e.g. as a nasal spray or aerosol for inhalation), nasal, parenteral (e.g. by an injectable form), gastrointestinal, intraspinal, intraperitoneal, intramuscular, intravenous, intrauterine, intraocular, intradermal, intracranial, intratracheal, intravaginal, intracerebroventricular, intracerebral, subcutaneous, ophthalmic (including intravitreal or intracameral), transdermal, rectal, buccal, vaginal, epidural, sublingual.
  • oral e.g. as a tablet, capsule, or as an ingestable solution
  • mucosal e.g. as a nasal spray or aerosol for inhalation
  • nasal parenteral (e.g. by an injectable form)
  • gastrointestinal intraspinal, intraperitoneal
  • a physician will determine the actual dosage which will be most suitable for an individual subject.
  • the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the individual undergoing therapy.
  • the formulations may be packaged in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water, for administration.
  • Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules and tablets of the kind previously described.
  • Exemplary unit dosage formulations contain a daily dose or unit daily sub-dose, or an appropriate fraction thereof, of the active ingredient.
  • Chemical synthesis The compounds described herein may be prepared by chemical synthesis techniques. It will be apparent to those skilled in the art that sensitive functional groups may need to be protected and deprotected during synthesis of a compound. This may be achieved by conventional techniques, for example as described in "Protective Groups in Organic Synthesis” by T W Greene and P G M Wuts, John Wiley and Sons Inc. (1991), and by P.J.Kocienski, in “Protecting Groups", Georg Thieme Verlag (1994).
  • any stereocenters present could, under certain conditions, be epimerized, for example if a base is used in a reaction with a substrate having an optical center comprising a base-sensitive group. It should be possible to circumvent potential problems such as this by choice of reaction sequence, conditions, reagents, protection/deprotection regimes, etc. as is well-known in the art.
  • a derivative includes the chemical modification of a compound. Examples of such modifications include the replacement of a hydrogen by a halo group, an alkyl group, an acyl group or an amino group and the like. The modification may increase or decrease one or more hydrogen bonding interactions, charge interactions, hydrophobic interactions, van der Waals interactions and/or dipole interactions.
  • Analog This term encompasses any enantiomers, racemates and stereoisomers, as well as all pharmaceutically acceptable salts and hydrates of such compounds.
  • Alkyl refers to a branched or unbranched saturated hydrocarbyl radical.
  • the alkyl group comprises from 1 to 100, preferably 3 to 30, carbon atoms, more preferably from 5 to 25 carbon atoms.
  • alkyl refers to methyl, ethyl, propyl, butyl, pentyl, or hexyl.
  • Alkenyl refers to a branched or unbranched hydrocarbyl radical containing one or more carbon-carbon double bonds.
  • the alkenyl group comprises from 2 to 30 carbon atoms, preferably from 5 to about 25 carbon atoms.
  • Alkynyl refers to a branched or unbranched hydrocarbyl radical containing one or more carbon-carbon triple bonds.
  • the alkynyl group comprises from about 3 to about 30 carbon atoms, for example from about 5 to about 25 carbon atoms.
  • Halogen refers to fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.
  • Cycloalkyl refers to an alicyclic moiety, suitably having 3, 4, 5, 6, 7 or 8 carbon atoms.
  • the group may be a bridged or polycyclic ring system. More often cycloalkyl groups are monocyclic. This term includes reference to groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, bicyclo[2.2.2]octyl and the like.
  • Aryl refers to an aromatic carbocyclic ring system, suitably comprising 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or
  • Aryl may be a polycyclic ring system, having two or more rings, at least one of which is aromatic. This term includes reference to groups such as phenyl, naphthyl fluorenyl, azulenyl, indenyl, anthryl and the like.
  • Heteroalkyl groups include for example, alkyloxy groups and alky thio groups.
  • Heterocycloalkyl or heteroaryl groups herein may have from 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15 or 16 ring atoms, at least one of which is selected from nitrogen, oxygen, phosphorus, silicon and sulfur.
  • a 3- to 10-membered ring or ring system and more particularly a 5- or 6-membered ring which may be saturated or unsaturated.
  • oxiranyl selected from oxiranyl, azirinyl, 1 ,2-oxathiolanyl, imidazolyl, thienyl, furyl, tetrahydrofuryl, pyranyl, thiopyranyl, thianthrenyl, isobenzofuranyl, benzofuranyl, chromenyl, 2H-pyrrolyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolidinyl, benzimidazolyl, pyrazolyl, pyrazinyl, pyrazolidinyl, thiazolyl, isothiazolyl, dithiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, piperidyl, piperazinyl, pyridazinyl, morpholinyl, thiomorpholinyl,
  • Substituted unless specified otherwise, signifies that one or more, especially up to 5, more especially 1, 2 or 3, of the hydrogen atoms in said moiety are replaced independently of each other by the corresponding number of substituents.
  • optionally substituted as used herein includes substituted or unsubstituted. It will, of course, be understood that substituents are only at positions where they are chemically possible, the person skilled in the art being able to decide (either experimentally or theoretically) without inappropriate effort whether a particular substitution is possible. For example, amino or hydroxy groups with free hydrogen may be unstable if bound to carbon atoms with unsaturated (e.g. olefinic) bonds.
  • the term “substituted” signifies one or more, especially up to 5, more especially 1, 2 or 3, of the hydrogen atoms in said moiety are replaced independently of each other by the corresponding number of substituents selected from OH, SH, NH2, halogen, cyano, carboxy, alkyl, cycloalkyl, aryl and heteroaryl.
  • substituents described herein may themselves be substituted by any substituent, subject to the aforementioned restriction to appropriate substitutions as recognized by the skilled person.
  • any of the aforementioned substituents may be further substituted by any of the aforementioned substituents, each of which may be further substituted by any of the aforementioned substituents.
  • Substituents may suitably include halogen atoms and halomethyl groups such as CF 3 and CCl 3 ; oxygen containing groups such as oxo, hydroxy, carboxy, carboxyalkyl, alkoxy, alkoyl, alkoyloxy, aryloxy, aryloyl and aryloyloxy; nitrogen containing groups such as amino, alkylamino, dialkylamino, cyano, azide and nitro; sulfur containing groups such as thiol, alkylthiol, sulfonyl and sulfoxide; heterocyclic groups which may themselves be substituted; alkyl groups, which may themselves be substituted; and aryl groups, which may themselves be substituted, such as phenyl and substituted phenyl.
  • oxygen containing groups such as oxo, hydroxy, carboxy, carboxyalkyl, alkoxy, alkoyl, alkoyloxy, aryloxy,
  • Alkyl includes substituted and unsubstituted benzyl. More preferably, “substituted” signifies substitution by one or more groups selected from OH, SH, NH 2 , halogen, cyano, oxo, carboxy, C(O)NH 2 C 1–6 alkyl, C 1–6 alkoxy, C(O)C 1–6 alkyl, C 1–6 alkylthio, C 1–5 heteroalkyl, C 1–5 heteroalkoxy, C 3–6 cycloalkyl, C 3–6 cycloalkoxy, C 6–10 aryl, C 6–10 aryloxy, C 5–10 heteroaryl and C 5–10 heteroaryloxy, of which the SH, NH 2 , C(O)NH 2 , C 1–6 alkyl, C 1–6 alkoxy, C(O)C 1–6 alkyl, C 1–6 alkylthio, C 1–5 heteroalkyl, C 1–5 heteroal
  • NanoHPLC-HR-MS chromatographic separation was carried out on an Acclaim PepMap RSLC column (50 ⁇ m x 15 cm, particle size 2 ⁇ m, pore size, 100 ⁇ , Thermo Scientific) with a gradient program from 95% A (0.1% FA), 5 % B (ACN 0.1 % FA) to 5 % A, 95 % B in 45 minutes on an Easy nanoLC 1000 (Thermo Scientific). Sample clean up and concentration was carried out with a pre column Acclaim PepMAP 100 (75 ⁇ m x 2 cm, particle size 3 ⁇ m, pore size 100 ⁇ ; Thermo Scientific) mounted on the system.
  • the LC system was coupled to a Q-Exactive mass spectrometer (Thermo Fisher) via a Nano Flex ion source (Thermo Scientific). Ionization was carried out with 2 kV of spray voltage, 250 °C of capillary temperature, 60 S-lens RF level. Mass spectrometry was working in Single ion Monitoring mode (SIM) following the mass range reported in Table 1. The detector was working in positive ion mode with the following parameters: resolution 70000 (FWHM at 400 m/z), AGC target 5 x 10 4 , and maximum injection time 200 ms. Data analysis was carried out with Thermo Xcalibur Qual Broswer v2.2 (Thermo Scientific) and Prism8 (GrapPhad).
  • RP-HPLC reversed-phase high-pressure liquid chromatography
  • Example 1 Preparation of “ESV6-NODAGA” and labelling Synthesis Synthesis of Intermediate I-1
  • 8-aminoquinoline-4-carboxylic acid 100 mg, 0.531 mmol, 1 eq
  • (S)-1- (2-aminoacetyl)-4.4-difluoropyrrolidine-2-carbonitrile hydrochloride 132 mg, 0.585 mmol, 1.1 eq
  • HATU 202 mg, 0.531 mmol, 1 eq
  • the dried crude was purified via CombiFlash Nextgen 300+ (parameters: flow 30 ml/min, 24 gr silica column, DMC/MeOH 90:10 to 70:30 in 4 minutes) to obtain an amber oil (58 mg, 95% yield).
  • AIF3 (1 mg, 11.6 pmol, 10 eq.) was added and the mixture was heated at 95°C for 15 min. Then the mixture was purified via RP-HPLC (95:5 to 0:100 water/ACN + 0.1% TFA in 20 min) the desired fractions were collected and lyophilized to afford a white solid. (0.8 mg, 80%).
  • ESV6-NOTA-A1-F (A1F@1)
  • AlF 3 (1 mg, 11.6 ⁇ mol, 10 eq.) was added and the mixture was heated at 95°C for 15 min. Then the mixture was purified via RP-HPLC (95:5 to 0:100 water/ACN + 0.1% TFA in 20 min) the desired fractions were collected and lyophilized to afford a white solid. (0.8 mg, 80%).
  • 13 C4-ESV6-NODAGA-Al-F was generated following the same procedure described for ESV6- NODAGA-Al-F, using 13 C 4 succinic anhydride as isotopically labelled building block for the synthesis of 1.
  • 13C4-ESV6-NOTA-Al-F was generated following the same procedure described for ESV6-NOTA-Al-F, using 13 C4 succinic anhydride as isotopically labelled building block for the synthesis of 1.
  • Example 3 Ex vivo characterization of “ESV6-NODAGA-Al-F” and of “ESV6-NOTA-Al- F” All animal experiments were conducted in accordance with Swiss animal welfare laws and regulations under the license number ZH06 / 2021 granted by the Veterinäramt des Kantons Zürich. Implantation of subcutaneous tumors Tumor cells were grown to 80% confluence and detached with Trypsin-EDTA 0.05%. SK-RC-52.hFAP, cells (FAP positive cells) were resuspended in Hanks’ Balanced Salt Solution medium.
  • mice tissues were resuspended in 600 ⁇ L of a solution containing 95 % ACN and 0.1 % FA to induce protein precipitation.
  • a solution 600 nM of internal standard 13 C 4 -ESV6- NODAGA-Al-F or 13 C 4 -ESV6-NOTA-Al-F
  • Samples were then homogenized with a tissue lyser (TissueLyser II, QIAGEN) for 15 minutes at 30 Hz. After homogenization, samples were centrifugated at 14000 g for 10 minutes and supernatants were dried at room temperature with a vacuum centrifuge.
  • Samples were then resuspended in 1 mF solution containing 3% ACN and 0.1 % of TFA and subsequently cleaned up using Oasis HLB SPE columns (Waters). Eluted samples were again dried under vacuum at room temperature, resuspended in 1 mL 3% ACN and 0.1 % of TFA and cleaned up using Sep-Pak SPE columns (Waters). Eluted samples were then dried under vacuum at room temperature.
  • Chromatographic separation was carried out on an Acclaim PepMap RSLC column (50 pm x 15 cm, particle size 2 pm, pore size, 100 A) with a gradient program from 95% A (0.1% FA), 5 % B (ACN 0.1 % FA) to 5 % A, 95 % B in 45 minutes on an Easy nanoEC 1000.
  • Sample clean up and concentration was carried out with a pre column Acclaim PepMAP 100 (75 pm x 2 cm, particle size 3 pm, pore size 100 A) mounted on the system.
  • the EC system was coupled to a Q-Exactive mass spectrometer via a Nano Flex ion source. Ionization was carried out with 2 kV of spray voltage, 250 °C of capillary temperature, 60 S- lens RF level.
  • Mass spectrometry was working in Single ion Monitoring mode (SIM) following the mass range reported in Table 1.
  • the detector was working in positive ion mode with the following parameters: resolution 70000 (FWHM at 400 m/z), AGC target 5 x 10 4 , and maximum injection time 200 ms.
  • Data analysis was carried out with Thermo Xcalibur Qual Broswer v2.2 and Prism8.
  • Table 1 Mass range windows for the SIM mode of the mass spectrometer.
  • HT-1080.hFAP cells FAP positive tumor cells
  • Cells were resuspended in Hanks’ Balanced Salt Solution medium.
  • Aliquots of 5 x 10 6 cells 100 pL of suspension were injected subcutaneously in the right flanks of female athymic Balb/c AnNRj-Foxnl mice (6 to 8 wk of age).
  • mice Female athymic Balb/c AnNRj-Foxnl mice (6 to 8 wk of age) implanted in the right flank with HT- 1080.hFAP tumors as described above were allowed to grow to an average tumor volume of 250 mm 3 .
  • Radiolabelling of ESV6-NOTA (200-300 pg) with 18 F was performed via aluminium (Al 3+ ) fluoride complex using FASTlab 2 synthesis module and the cassette.
  • [ 18 F] -fluoride was transferred to the module and trapped on a Sep-Pak light Accel plus QMA cartridge (Cl- form:). The cartridge was washed with 6 mL of water (HPCE grade).
  • [ 18 F] -fluoride was eluted from the QMA cartridge into reactor vessel with 500 pL of the eluent solution (250 pL NaCl 0.9%; 99.999% trace metals basis NaCl;) in water for injection and 250 pL absolute ethanol). The solution was stirred for 5 min at room temperature under gentle nitrogen flow to form [ 18 F]A1F. The precursor solution (600 pL of 350 pg/mL ESV6-NOTA in sodium acetate 0.1M pH 4.5) was added to the reactor which was sealed and heated for 10 min at 95°C.
  • the precursor solution 600 pL of 350 pg/mL ESV6-NOTA in sodium acetate 0.1M pH 4.5
  • Example 5 Radiosynthesis of [ 68 Ga]GaESV6-NODAGA and of [ 68 Ga]GaESV6-NOTA
  • Example 6 Characterization of r 68 Ga1GaESV6-NODAGA, [ 68 Ga1GaESV6-NOTA and of ESV6- NOTA-[ 18 F1A1-F binding to human FAP

Abstract

La présente invention concerne des ligands de la protéine d'activation des fibroblastes (FAP) pour l'administration active de charges utiles radioactives au niveau du site de la maladie. En particulier, la présente invention concerne le développement de ligands FAP pour l'administration ciblée de radionucléides, tels que 18fluor, 68gallium, 64cuivre, 111indium, 177lutécium, et des méthodes diagnostiques et/ou des méthodes thérapeutiques ou chirurgicales associées à une maladie ou un trouble, de type cancer, inflammation ou autre maladie caractérisée par la surexpression de la FAP.
PCT/EP2022/077598 2021-10-04 2022-10-04 Ligands de protéine d'activation des fibroblastes radiomarqués WO2023057457A1 (fr)

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Publication number Priority date Publication date Assignee Title
CN116925041A (zh) * 2023-06-12 2023-10-24 上海交通大学医学院附属仁济医院 靶向成纤维细胞激活蛋白的氟标记放射性药物前体、放射性标记化合物及其应用

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