WO2023209141A1 - Benzo[d]imidazo[1,2-a]imidazoles et leur utilisation dans le diagnostic - Google Patents

Benzo[d]imidazo[1,2-a]imidazoles et leur utilisation dans le diagnostic Download PDF

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WO2023209141A1
WO2023209141A1 PCT/EP2023/061215 EP2023061215W WO2023209141A1 WO 2023209141 A1 WO2023209141 A1 WO 2023209141A1 EP 2023061215 W EP2023061215 W EP 2023061215W WO 2023209141 A1 WO2023209141 A1 WO 2023209141A1
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alkyl
compound
label
formula
linker
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PCT/EP2023/061215
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English (en)
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Andreas Faust
Johannes Roth
Thomas Vogl
Sven Hermann
Simon STEINER
Michael SCHÄFERS
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Westfälische Wilhelms-Universität Münster
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Publication of WO2023209141A1 publication Critical patent/WO2023209141A1/fr

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    • 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
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to compounds of formula (I) comprising a label, and their use in diagnosis.
  • the present invention further relates to a method of diagnosing an inflammatory disease in a subject, comprising (a) administering a compound of formula (I) comprising a label, (b) detecting the administered compound using in vivo non-invasive molecular imaging techniques, thereby collecting imaging data, and (c) comparing the imaging data received in step (b) to reference imaging data.
  • a non-invasive method of detecting or imaging accumulation of S100A9 in the body of a subject to whom a compound of formula (I) comprising a label has been pre-delivered is also provided.
  • the present invention is further directed to the use of a compound of formula (I) comprising a label for the preparation of a diagnostic composition for diagnosing an inflammatory process.
  • a method for evaluating whether a subject may be at risk of developing an inflammatory disease associated with phagocyte and/or epithelial cell activation and S100A9 accumulation is also envisaged.
  • the present invention also relates to a method of monitoring or evaluating the progression of an inflammatory reaction in a patient.
  • a method of imaging an inflammatory disease associated with phagocyte and/or epithelial cell activation in a subject is further comprised by the present invention.
  • Provided is also an in vitro method of diagnosing an inflammatory disease in a subject to whom a compound of formula (I) comprising a label has been pre-delivered.
  • Inflammatory diseases are of high relevance in daily clinical practise and often dominated and driven by activated phagocytes.
  • the alarmin S100A8/S100A9 is expressed and secreted in high concentrations by immigrating phagocytes at sites of inflammation and is known to trigger sterile as well as infectious inflammatory processes.
  • S100A8 and S100A9 belong to the S100-family of Ca 2+ -binding proteins and are involved in many immune processes. The physiological relevant forms are heterodimers and upon calcium-binding heterotetramers, both forms are also described as calprotectin.
  • S100A8/S100A9 complexes promote inflammatory processes but helps also in tissue repair or immune defence reactions by interaction with TLR4 and other receptors.
  • Inflammation is the driving force in a broad spectrum of clinically relevant disorders and disease severity often correlates with the number of immigrated activated phagocytes.
  • the alarmin S100A8/A9 is highly expressed and locally secreted by activated phagocytes at an early stage in the inflammatory cascade enabling early and sensitive detection of inflammation.
  • High local S100A8/A9 concentrations arise at the site of inflammation and are typically up to 50-fold higher than those occurring in the systemic circulation. Therefore, the local assessment of S100A8/A9 by imaging strategies as surrogate marker for phagocyte activity is of interest to provide sensitive and specific monitoring of changes in the local expression of these molecules and thus of inflammatory activity.
  • S100A9 subunit of the heterodimeric complex is a valuable and sensitive phagocyte marker for quantifying inflammatory disease activities (Vogl T, Eisenblatter M, Voller T, Zenker S, Hermann S, van Lent P, Faust A, Geyer C, Petersen B, Roebrock K, Schafers M, Bremer C, Roth J. Alarmin S100A8/S100A9 as a biomarker for molecular imaging of local inflammatory activity.
  • the present invention relates to a compound of formula (I) or a salt, isomer, or tautomer thereof; wherein
  • R A , R B , and R c are each independently selected from H, halogen, cyano, RTO, C1-C6 alkyl optionally substituted by RTO, C3-C6 cycloalkyl optionally substituted by R-iO, R 2 C(O), R 3 S, R 4 S(O) 2 , R 5 OC(O), (R 6 ON)C(R 7 ), R 8 R 9 NC(O), R10R11N, RI 2 S(O) 2 NR 13 , RI 4 S(O) 2 NR 15 C(O), phenyl optionally substituted by one or more moieties R 16 , and 5- or 6-membered heterocyclyl optionally substituted by one or more moieties R 16 ; or one of R A and R c together with R B forms a group -(CH 2 ) m - wherein m is an integer of from 3 to 5, and the other one of R A and R c is selected from H, halogen, cyano
  • R L is a linker; and R L is a label.
  • the present invention also relates to a diagnostic composition
  • a diagnostic composition comprising a compound according to the invention and a pharmaceutically or diagnostically acceptable excipient.
  • the present invention also relates to a compound according to the invention for use in a method of diagnosis.
  • the diagnosis may be diagnosis of an inflammatory disease in a subject.
  • the present invention also relates to a method of diagnosing an inflammatory disease in a subject, comprising: a) administering to said subject a compound according to the invention, b) detecting the administered compound using an in vivo non-invasive molecular imaging technique, thereby collecting imaging data, c) comparing the imaging data received in step b) to reference imaging data.
  • the present invention also relates to a non-invasive method of detecting or imaging accumulation of S100A9 in the body of a subject to whom a compound of the invention has been pre-delivered, comprising: a) detecting the administered compound using an in vivo non-invasive molecular imaging technique, thereby collecting imaging data, b) comparing the imaging data received in step a) to reference imaging data.
  • the present invention also relates to the use of a compound according to the invention for the preparation of a diagnostic composition for diagnosing an inflammatory disease associated with phagocyte and/or epithelial cell activation in a subject.
  • the present invention also relates to a method for evaluating whether a subject may be at risk of developing an inflammatory disease associated with phagocyte and/or epithelial cell activation, the method comprising: a) administering to said subject a compound according to the invention, b) detecting the administered compound using an in vivo non-invasive molecular imaging technique, thereby collecting imaging data, c) comparing the imaging data received in step b) to reference imaging data.
  • the present invention also relates to a method of monitoring or evaluating the progression of an inflammatory disease associated with phagocyte and/or epithelial cell activation in a patient, the method comprising: a) administering to said subject a compound according to the invention, b) detecting the administered compound using an in vivo non-invasive molecular imaging technique, thereby collecting imaging data, c) comparing the imaging data received in step b) to reference imaging data obtained from said patient at an earlier date, wherein the result of the comparison of c) provides an evaluation of the progression of the inflammatory disease associated with phagocyte and/or epithelial cell activation in said patient.
  • the present invention also relates to a method of imaging an inflammatory disease in a subject, comprising: a) administering to said subject a compound according to the invention, b) detecting the administered compound using an in vivo non-invasive molecular imaging method, thereby collecting imaging data.
  • the present invention also relates to an in vitro method of diagnosing an inflammatory disease in a subject to whom a compound according to the invention has been pre-delivered, comprising: a) analyzing a sample taken from said subject, b) detecting said pre-delivered compound using a non-invasive molecular imaging method, thereby collecting imaging data, c) comparing the imaging data received in step b) to reference imaging data.
  • the present invention also relates to a process for the preparation of a compound of the formula (I*) or its salts, isomers, tautomers or solvates thereof, comprising reacting a compound of the formula (X*) with a compound of the formula (XI) and a compound of the formula (XII) to give a compound of the formula (I*) wherein R 500 is C1-C6 alkyl, preferably methyl or ethyl, more preferably ethyl;
  • L* is a linker capable of forming a covalent attachment to a label R L ;
  • L* is a part of a linker capable of forming a covalent attachment to another part of a linker
  • R A , R B and R c are as defined herein.
  • the present invention also relates to a process for the preparation of a compound of the formula (I) or its salts, isomers, tautomers or solvates thereof, as described herein, comprising reacting a compound of the formula (X) and a compound of the formula (XII) to give a compound of the formula (I) wherein R 500 is C1-C6 alkyl, preferably methyl or ethyl, more preferably ethyl; and RA, B, RC, L and R L are as defined herein.
  • Figure 1 shows in vivo imaging using the compound Cy5.5-SST110 in an ear inflammation mouse model of irritant contact dermatitis.
  • Figure 2 shows the murine and human blood serum stability of the compound [ 18 F]SST034 over 120 min.
  • Figure 3 shows the murine and human blood serum stability of the compound [ 18 F]SST096 over 120 min.
  • Figure 4 shows the murine and human blood serum stability of the compound [ 18 F]SST120 over 120 min.
  • Figure 5 shows in vivo biodistribution studies with the compound [ 18 F]SST034.
  • Figure 5A shows maximum intensity projections of selected time frames (in vivo).
  • Figure 5B shows an ex vivo gamma counter analysis (110 min p.i.).
  • Figure 6 shows in vivo biodistribution studies with the compound [ 18 F]SST096.
  • Figure 6A shows Maximum Intensity Projections of selected time frames (in vivo).
  • Figure 6B shows an ex vivo gamma counter analysis (110 min p.i.).
  • Figure 7 shows in vivo biodistribution studies with the compound [ 18 F]SST120.
  • Figure 7A shows Maximum Intensity Projections of selected time frames (in vivo).
  • Figure 7B shows an ex vivo gamma counter analysis (110 min p.i.).
  • Figure 8 shows three separate runs for determining the equilibrium binding constant K d of fluorescein-labelled derivative 6-FAM-SST177 towards mS100A9 in accordance with Example 2. Depicted is the fluorescence intensity (Fl, vertical axis) depending of the concentration of mS100A9 in pM (horizontal axis).
  • Figure 9 shows saturation binding curves (“one-site - specific binding” model) determining the K D of AF488-SST193 towards A) mS100A9 in HPS buffer, B) mS100A9 in Tris buffer, C) hS100A9C3S in Tris buffer and D) mS100A8 in HPS buffer as a negative control.
  • Each curve refers to an individual experiment with date given in the legend.
  • the conjunctive term "and/or" between multiple recited elements is understood as encompassing both individual and combined options. For instance, where two elements are conjoined by "and/or", a first option refers to the applicability of the first element without the second. A second option refers to the applicability of the second element without the first. A third option refers to the applicability of the first and second elements together. Any one of these options is understood to fall within the meaning, and therefore satisfy the requirement of the term "and/or” as used herein. Concurrent applicability of more than one of the options is also understood to fall within the meaning, and therefore satisfy the requirement of the term "and/or” as used herein.
  • the word “about” as used herein refers to a value being within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, “about” can mean within 1 or more than 1 standard deviation, per the practice in the art. The term “about” is also used to indicate that the amount or value in question may be the value designated or some other value that is approximately the same. The phrase is intended to convey that similar values promote equivalent results or effects according to the invention. In this context “about” may refer to a range above and/or below of up to 10%.
  • the word “about” refers in some embodiments to a range above and below a certain value that is up to 5%, such as up to up to 2%, up to 1%, or up to 0.5 % above or below that value. In one embodiment “about” refers to a range up to 0.1 % above and below a given value.
  • the present invention is, at least partly, based on the surprising finding that compounds of formula (I) comprising a label, i.e. compounds comprising a benzimidazole moiety, are well suited for diagnostic use.
  • the present invention demonstrates that compounds of formula (I) comprising a label are applicable for use in the diagnosis of an inflammatory disease associated with accumulation of S100A9 at local site of inflammation, using non-invasive molecular imaging techniques for detecting said compounds in vivo.
  • the inventors of the present application surprisingly found that compounds of formula (I) comprising a label can thus be used for diagnosing inflammatory diseases with high molecular sensitivity. This can be explained by specific binding of the compounds to S100A9.
  • the compounds may not bind to or interact with S100A8, or may bind to or interact with S100A8 only to a low extent.
  • the results presented herein were unforeseeable.
  • WO 2015/177367 A1 describes benzo[d]imidazo[1,2-a]imidazole compounds exclusively for therapeutic use in the therapeutic treatment of diseases.
  • a diagnostic approach using compounds in which a benzo[d]imidazo[1,2-a]imidazole moiety is covalently linked to a label has never been reported so far.
  • an optical (fluorescent) probe based on the S100A9 ligand benzo[d]imidazo[1,2-a]imidazole could be successfully synthesised.
  • Imaging experiments in a mouse models showed significant accumulation at the sites of inflammatory active diseases, e.g. in a mouse models of dermatitis.
  • the inventors have further demonstrated stability of radiotracers in murine and human blood serum over the time. Further, biodistribution studies have been carried out indicating properties favorable for diagnostic applications in vivo.
  • the present invention is at least partly based on the surprising fact that compounds of formula (I) comprising a label are well suited for use in diagnosis of inflammatory diseases associated with an increased phagocyte and/or epithelial cell activity and an increased accumulation of S100A9.
  • these compounds could be successfully used for in vivo non-invasive molecular imaging in a model of dermatitis.
  • the present invention relates to a compound of formula (I) or a salt, isomer, or tautomer thereof; wherein
  • R A , R B , and R c are each independently selected from H, halogen, cyano, RTO, C1-C6 alkyl optionally substituted by RTO, C3-C6 cycloalkyl optionally substituted by R-iO, R 2 C(O), R 3 S, R 4 S(O) 2 , R 5 OC(O), (R 6 ON)C(R 7 ), R 8 R 9 NC(O), R10R11N, RI 2 S(O) 2 NR 13 , RI 4 S(O) 2 NR 15 C(O), phenyl optionally substituted by one or more moieties R 16 , and 5- or 6-membered heterocyclyl optionally substituted by one or more moieties R 16 ; or one of R A and R c together with R B forms a divalent group -(CH 2 ) m - wherein m is an integer of from 3 to 5, and the other one of R A and R c is selected from H, halogen,
  • each R 16 is independently selected from halogen, cyano, nitro, RI 7 O, C1-C6 alkyl optionally substituted by RI 7 O, C3-C6 cycloalkyl optionally substituted by RI 7 O, RI 8 C(O), R 19 S, R 20 S(O) 2 , R 2 IOC(O), (R 22 ON)C(R 23 ), R 24 R 25 NC(O), R 26 R 27 N, R 28 S(O) 2 NR 29 , and R 3 OS(0) 2 NR 31 C(0); each one of R1-R15 and RI 7 -R 3 I is independently selected from H, C1-C6 alkyl, and C3-C6 cycloalkyl;
  • L is a linker
  • R L is a label.
  • R A , R B and R c are independently selected from H, halogen, cyano, RTO, C1-C6 alkyl optionally substituted by RTO, C3-C6 cycloalkyl optionally substituted by RA R 2 C(O), R 3 S, R 4 S(O) 2 , R 5 OC(O), (R 6 ON)C(R 7 ), R 8 R 9 NC(O), R RnN, RI 2 S(O) 2 NR 13 , R 14 S(O) 2 NR 15 C(O), phenyl optionally substituted by one or more moieties R 16 , and 5- or 6-membered heterocyclyl optionally substituted by one or more moieties R 16 .
  • one of R A and R c together with R B forms a divalent group -(CH 2 ) m - wherein m is an integer of from 3 to 5, and the other one of R A and R c is selected from H, halogen, cyano, RA C1-C6 alkyl optionally substituted by RA C3-C6 cycloalkyl optionally substituted by RA R 2 C(O), R 3 S, R 4 S(O) 2 , R 5 OC(O), (R 6 ON)C(R 7 ), R 8 R 9 NC(O), R10R11N, R 12 S(O) 2 NR 13 , R 14 S(O) 2 NR 15 C(O), phenyl optionally substituted by one or more moieties R 16 , and 5- or 6-membered heterocyclyl optionally substituted by one or more moieties R 16 .
  • the moiety R A may be selected from H, halogen, cyano, RA C1-C6 alkyl optionally substituted by RA C3-C6 cycloalkyl optionally substituted by R R 2 C(O), R 3 S, R 4 S(O) 2 , R 5 OC(O), (R 6 ON)C(R 7 ), R 8 R 9 NC(O), R10R11N, RI 2 S(O) 2 NR 13 , R 14 S(O) 2 NR 15 C(O), phenyl optionally substituted by one or more moieties R 16 , and 5- or 6-membered heterocyclyl optionally substituted by one or more moieties R 16 ; or forms together with R B a divalent group -(CH 2 ) m - wherein m is an integer of from 3 to 5.
  • R A is selected from H, halogen, cyano, RA C1-C6 alkyl optionally substituted by RA C3-C6 cycloalkyl optionally substituted by R R 2 C(O), R 3 S, R 4 S(O) 2 , R 5 OC(O), (R 6 ON)C(R 7 ), R 8 R 9 NC(O), R10R11N, RI 2 S(O) 2 NR 13 , R 14 S(O) 2 NR 15 C(O), phenyl optionally substituted by one or more moieties R 16 , and 5- or 6-membered heterocyclyl optionally substituted by one or more moieties R 16 .
  • R A is selected from H, halogen, cyano, RA C1-C6 alkyl optionally substituted by RA C3-C6 cycloalkyl optionally substituted by R R 2 C(O), R 3 S, R 4 S(O) 2 , R 5 OC(O), (R 6 ON)C(R 7 ), R 8 R 9 NC(O), R10R11N, RI 2 S(O) 2 NR 13 , and
  • R A is selected from H, halogen, cyano, C1-C6 alkyl optionally substituted by RA C3-C6 cycloalkyl optionally substituted by RA R 2 C(O), R 3 S, R 4 S(O) 2 , R 5 OC(O), RI 2 S(O) 2 NR 13 , and R 14 S(O) 2 NR 15 C(O).
  • R A is selected from H, halogen, C1-C6 alkyl and R 2 C(O), e.g.
  • R A is H.
  • R A is selected from halogen, C1-C6 alkyl and R 2 C(O), e.g. C1 -C6 alkyl and R 2 C(O), e.g. R A is R 2 C(O), or R A is C1-C6 alkyl.
  • R A is selected from H, halogen, cyano, C1-C6 alkyl, C3-C6 cycloalkyl, R 2 C(O), R 4 S(O) 2 , R 5 OC(O), RI 2 S(O) 2 NR 13 , R 14 S(O) 2 NR 15 C(O), phenyl optionally substituted by one or more moieties R 16 , and 5- or 6-membered heterocyclyl optionally substituted by one or more moieties R 16 ; e.g.
  • R A when R A is phenyl optionally substituted by one or more moieties R 16 , or 5- or 6-membered heterocyclyl optionally substituted by one or more moieties R 16 , it more particularly is phenyl optionally substituted by one or more moieties R 16 . In some embodiments, when R A is phenyl optionally substituted by one or more moieties R 16 , or 5- or 6-membered heterocyclyl optionally substituted by one or more moieties R 16 , it more particularly is 5- or 6-membered heterocyclyl optionally substituted by one or more moieties Rl6-
  • the moiety R B may be selected from H, halogen, cyano, RTO, C1-C6 alkyl optionally substituted by RTO, C3-C6 cycloalkyl optionally substituted by RTO, R 2 C(O), R 3 S, R 4 S(O) 2 , R 5 OC(O), (R 6 ON)C(R 7 ), R 8 R 9 NC(O), R RuN, RI 2 S(O) 2 NR 13 , R 14 S(O) 2 NR 15 C(O), phenyl optionally substituted by one or more moieties R 16 , and 5- or 6-membered heterocyclyl optionally substituted by one or more moieties R 16 ; or may form together with either R A or R c a divalent group -(CH 2 ) m - wherein m is an integer of from 3 to 5.
  • R B is selected from H, halogen, cyano, RTO, C1 -C6 alkyl, optionally substituted by RTO, C3-C6 cycloalkyl optionally substituted by R1O, R 2 C(O), R 3 S, R 4 S(O) 2 , R 5 OC(O), (R 6 ON)C(R 7 ), R 8 R 9 NC(O), R10R11N, RI 2 S(O) 2 NR 13 , R 14 S(O) 2 NR 15 C(O), phenyl optionally substituted by one or more moieties R 16 , and 5- or 6-membered heterocyclyl optionally substituted by one or more moieties R 16 .
  • R B is selected from H, halogen, RTO, C1-C6 alkyl optionally substituted by RTO, C3-C6 cycloalkyl optionally substituted by RTO, phenyl optionally substituted by one or more moieties R 16 , and 5- or 6-membered heterocyclyl optionally substituted by one or more moieties R 16 .
  • R B is phenyl optionally substituted by one or more moieties R 16 , or 5- or 6-membered heterocyclyl optionally substituted by one or more moieties R 16 .
  • R B is selected from H, halogen, RTO, C1-C6 alkyl optionally substituted by RTO, and C3-C6 cycloalkyl optionally substituted by RTO, e.g. from H, halogen, and C1-C6 alkyl optionally substituted by RTO.
  • R B is selected from H, halogen, C1-C6 alkyl optionally substituted by RTO, and C3-C6 cycloalkyl optionally substituted by RTO, e.g. from H and halogen.
  • R B is selected from H, halogen, C1-C6 alkyl and C3-C6 cycloalkyl, e.g. from H, halogen, and C1-C6 alkyl, e.g. from H and C1-C6 alkyl.
  • R B is selected from halogen, C1-C6 alkyl optionally substituted by RTO, and C3-C6 cycloalkyl optionally substituted by RTO, e.g. from halogen, and C1-C6 alkyl optionally substituted by RTO; or from halogen, and C1-C6 alkyl, e.g. R B is halogen.
  • R B is H.
  • the moiety R c may be selected from H, halogen, cyano, RTO, C1-C6 alkyl optionally substituted by RTO, C3-C6 cycloalkyl optionally substituted by RTO, R 2 C(O), R 3 S, R 4 S(O) 2 , R 5 OC(O), (R 6 ON)C(R 7 ), R 8 R 9 NC(O), R RuN, RI 2 S(O) 2 NR 13 , RI 4 S(O) 2 NR 15 C(O), phenyl optionally substituted by one or more moieties R 16 , and 5- or 6-membered heterocyclyl optionally substituted by one or more moieties R 16 , or may form together with R B a divalent group -(CH 2 ) m - wherein m is an integer of from 3 to 5.
  • R c is selected from H, halogen, cyano, RTO, C1-C6 alkyl optionally substituted by RTO, C3-C6 cycloalkyl optionally substituted by R1O, R 2 C(O), R 3 S, R 4 S(O) 2 , RSOC(O), (R 6 ON)C(R 7 ), R 8 R 9 NC(O), R10R11N, R 12 S(O) 2 NR 13 , RI 4 S(O) 2 NR 15 C(O), phenyl optionally substituted by one or more moieties R 16 , and 5- or 6-membered heterocyclyl optionally substituted by one or more moieties R 16 .
  • R c is selected from H, halogen, RTO, C1-C6 alkyl optionally substituted by RTO, C3-C6 cycloalkyl optionally substituted by RTO, R 2 C(O), phenyl optionally substituted by one or more moieties R 16 , and 5- or 6-membered heterocyclyl optionally substituted by one or more moieties R 16 .
  • R c is phenyl optionally substituted by one or more moieties R 16 , or 5- or 6-membered heterocyclyl optionally substituted by one or more moieties R 16 .
  • R c is selected from H, halogen, RTO, C1-C6 alkyl optionally substituted by RTO, C3-C6 cycloalkyl optionally substituted by RTO, and R 2 C(O).
  • R c is selected from H, halogen, RTO, C1-C6 alkyl optionally substituted by RTO, and C3-C6 cycloalkyl optionally substituted by RTO, e.g. from H, halogen, C1-C6 alkyl optionally substituted by RTO, and C3-C6 cycloalkyl optionally substituted by R1O, or from H, halogen, C1 -C6 alkyl, and C3-C6 cycloalkyl, in particular from H, halogen and C1-C6 alkyl, or from H and C1-C6 alkyl.
  • R c is H.
  • one of R A and R c forms together with R B a divalent group - (CH 2 ) m - wherein m is an integer of from 3 to 5, e.g. m is 3 or 4, or m is 3.
  • the other one of R A and R c may be selected from H, halogen, cyano, RTO, CI- 06 alkyl optionally substituted by RTO, C3-C6 cycloalkyl optionally substituted by RTO, R 2 C(O), R 3 S, R 4 S(O) 2 , R 5 OC(O), (R 6 ON)C(R 7 ), R 8 R 9 NC(O), R10R11N, RI 2 S(O) 2 NR 13 , RI 4 S(O) 2 NR 15 C(O), phenyl optionally substituted by one or more moieties R 16 , and 5- or 6- membered heterocyclyl optionally substituted by one or more moieties R 16 .
  • the other one of R A and R c preferably is selected from H, halogen, cyano, R1O, C1-C6 alkyl optionally substituted by RTO, C3-C6 cycloalkyl optionally substituted by R1O, R 2 C(O), R 3 S , R 4 S(O) 2 , R 5 OC(O), (R 6 ON)C(R 7 ), R 8 R 9 NC(O), R10R11N, RI 2 S(O) 2 NR 13 , and R 14 S(O) 2 NR 15 C(O); e.g.
  • At least one of R A , R B and R c is phenyl optionally substituted by one or more moieties R 16 , or 5- or 6-membered heterocyclyl optionally substituted by one or more moieties R 16 .
  • one of R A , R B and R c is phenyl optionally substituted by one or more moieties R 16 , or 5- or 6-membered heterocyclyl optionally substituted by one or more moieties R 16 .
  • R A , R B and R c when one of R A , R B and R c is phenyl optionally substituted by one or more moieties R 16 , or 5- or 6-membered heterocyclyl optionally substituted by one or more moieties R 16 , the two others of R A , R B and R c are as defined herein above, but are not phenyl optionally substituted by one or more moieties R 16 , or 5- or 6-membered heterocyclyl optionally substituted by one or more moieties R 16 .
  • R A , R B and R c when one of R A , R B and R c is phenyl optionally substituted by one or more moieties R 16 , or 5- or 6-membered heterocyclyl optionally substituted by one or more moieties R 16 , the two others of R A , R B and R c are selected from H, halogen, C1 -C6 alkyl, C3-C6 cycloalkyl and R 2 C(O), or from H, halogen C1-C6 alkyl and R 2 C(O), e.g. from H, F, Cl, and C1 -C3 alkyl; or from H, F and methyl; e.g. both are H or F, or both are H.
  • R A , R B and R c are independently selected from H, halogen, cyano, C1-C4 alkyl, RTO, R 2 C(O), R 3 S, and R 4 S(O) 2 ; or one of R A and R c , together with R B , forms a divalent group -(CH 2 ) m - wherein m is an integer of from 3 to 5, and the other one of R A and R c is selected from H, halogen, cyano, C1-C4 alkyl, RTO, R 2 C(O), R 3 S, and R 4 S(O) 2 .
  • R A , R B and R c when anyone of R A , R B and R c is selected from halogen, it more particularly may be selected from F, Cl or Br, or from F and Cl, in particular Cl.
  • R A , R B and R c when anyone of R A , R B and R c is selected from C1-C6 alkyl optionally substituted by R-iO and C3-C6 cycloalkyl optionally substituted by RTO, it more particularly may be selected from C1-C6 alkyl optionally substituted by RTO, e.g. from C1-C4 alkyl optionally substituted by RTO, or C1-C3 alkyl optionally substituted by RTO, in particular methyl optionally substituted by RTO.
  • R A , R B and R c when anyone of R A , R B and R c is selected from C1-C6 alkyl optionally substituted by RiO and C3-C6 cycloalkyl optionally substituted by RTO, it more particularly may be selected from C1-C6 alkyl, or from C1-C4 alkyl, or C1-C3 alkyl, in particular methyl.
  • R A , R B and R c when anyone of R A , R B and R c is selected from C3-C6 cycloalkyl optionally substituted by RTO, it more particularly may be selected from C3-C6 cycloalkyl, or from C3-C5 cycloalkyl, or from C3-C4 cycloalkyl, e.g. cyclopropyl.
  • R A , R B and Rc are all H, i.e. the compound of formula (I) is a compound of formula (la): wherein L and R L are as defined herein.
  • At least one of R A , R B and R c is different from H.
  • R A is as defined herein above, but is different from H; or R B is as defined herein above, but is different from H.
  • R A , R B and R c are different from H, i.e. R A and R B are different from H, or R A and R c are different from H, or R B and R c are different from H.
  • R A is H and the compound may then be represented by formula (lb) wherein R B , R c , L and R L are as defined herein, e.g. R B and R c are as defined herein above, but neither R B nor R c is H.
  • R A is different from H. In some embodiments, R A and R B are different from H and R c is H. In some other embodiments, R A and R c are different from H and R B is H.
  • R A is different from H and R B and R c are both H, i.e. the compound may be represented by formula (Ic) wherein R A , L and R L are as defined herein.
  • R-i when anyone of R A , R B , and R c is RTO, C1-C6 alkyl optionally substituted by RTO, or C3-C6 cycloalkyl optionally substituted by RTO, the moiety R-i may be selected from H, C1-C6 alkyl, and C3-C6 cycloalkyl, e.g. from H, C1-C4 alkyl, and C3-C4 cycloalkyl, or from H, C1-C3 alkyl and cyclopropyl. In some embodiments, the moiety R-i may be selected from H and C1-C6 alkyl, e.g. from H and C1-C4 alkyl, or from H and C1-C3 alkyl, such as from H and CH3, in particular H.
  • the moiety R-i is as defined herein above, but is not H; e.g. R-, is CH 3 .
  • R A , R B , and R c when anyone of R A , R B , and R c is selected from RTO, C1-C6 alkyl optionally substituted by RTO and C3-C6 cycloalkyl optionally substituted by RTO, it more particularly may be selected from RTO and C1-C6 alkyl optionally substituted by RTO, e.g. from RTO and C1-C3 alkyl optionally substituted by RTO, or from RTO and C1-C2 alkyl optionally substituted by RTO, e.g. it may be selected from RTO, RIOCH 2 , and R 1 OCH(CH 3 ), in particular RTO.
  • R 2 when anyone of R A , R B , and R c is R 2 C(O), R 2 may be H, CI- 06 alkyl, or C3-C6 cycloalkyl. In some embodiments, R 2 is selected from H, C1-C4 alkyl, and C3-C4 cycloalkyl, or from H, C1-C3 alkyl and cyclopropyl. In some embodiments, R 2 is selected from H and C1 -C6 alkyl, e.g. from H and 01-04 alkyl, or from H and 01-03 alkyl, such as from H, CH 3 and (CH 3 ) 2 CH, in particular CH 3 . In some embodiments, the moiety R 2 is as defined herein above, but is not H.
  • R 3 when anyone of R A , R B , and R c is R 3 S, R 3 may be H, 01-06 alkyl, or 03-06 cycloalkyl. In some embodiments, R 3 is selected from H, 01-04 alkyl, and 03-04 cycloalkyl, or from H, 01-03 alkyl and cyclopropyl. In some embodiments, R 3 is selected from H and 01-06 alkyl, e.g. from H and 01-04 alkyl, or from H and 01-03 alkyl, such as from H and CH 3 , in particular CH 3 . In some embodiments, the moiety R 3 is as defined herein above, but is not H.
  • R 4 when anyone of R A , R B , and R c is R4SO 2 , R 4 may be H, CI- 06 alkyl, or 03-06 cycloalkyl. In some embodiments, R 4 is selected from H, 01 -04 alkyl, and 03-04 cycloalkyl, or from H, 01-03 alkyl and cyclopropyl. In some embodiments, R 4 is selected from H and 01-06 alkyl, e.g. from H and 01 -04 alkyl, or from H and 01-03 alkyl, such as from H and CH 3 , in particular CH 3 . In some embodiments, the moiety R 4 is as defined herein above, but is not H.
  • R 5 when anyone of R A , R B , and R c is R 5 OC(O), R 5 may be H, CI- 06 alkyl, or 03-06 cycloalkyl. In some embodiments, R 5 is selected from H, 01-04 alkyl, and 03-04 cycloalkyl, or from H, 01-03 alkyl and cyclopropyl. In some embodiments, R5 is selected from H and 01-06 alkyl, e.g. from H and 01 -04 alkyl, or from H and 01 -03 alkyl, such as from H and CH 3 , in particular H.
  • R 6 when anyone of R A , R B , and R c is (R 6 ON)C(R 7 ), R 6 may be H, 01-06 alkyl, or 03-06 cycloalkyl. In some embodiments, R 6 is selected from H, 01 -04 alkyl, and 03-04 cycloalkyl, or from H, 01-03 alkyl and cyclopropyl. In some embodiments, R 6 is selected from H and 01-06 alkyl, e.g. from H and 01-04 alkyl, or from H and 01-03 alkyl, such as from H and CH 3 , in particular H. R 7 may be H, 01 -06 alkyl, and 03-06 cycloalkyl.
  • R 7 is selected from H, 01-04 alkyl, and 03-04 cycloalkyl, or from H, CI- 03 alkyl and cyclopropyl.
  • R 7 is selected from H and 01-06 alkyl, e.g. from H and 01 -04 alkyl, or from H and 01-03 alkyl, such as from H and CH 3 , in particular CH 3 .
  • the moiety R 7 is as defined herein above, but is not H.
  • R 6 is H and R 7 is as defined herein above, but different from H, e.g. R 7 is CH 3 .
  • each one of R 8 , R 9 , R 10 and Rn may be independently selected from H, C1-C6 alkyl, and C3-C6 cycloalkyl, e.g. from H, C1-C4 alkyl, and C3-C4 cycloalkyl, or from H, C1-C3 alkyl and cyclopropyl.
  • each one of R 8 , R 9 , R 10 and Rn may be independently selected from H and C1-C6 alkyl, e.g. from H and C1-C4 alkyl, or from H and C1-C3 alkyl, such as from H and CH 3 .
  • each one of R 12 , R 13 , R 14 and R 15 may be independently selected from H, C1-C6 alkyl, and C3-C6 cycloalkyl, e.g. from H, C1-C4 alkyl, and C3-C4 cycloalkyl, or from H, C1-C3 alkyl and cyclopropyl.
  • each one of R 12 , R 13 , R 14 and R 15 is independently selected from H and C1-C6 alkyl, e.g. from H and C1-C4 alkyl, or from H and C1-C3 alkyl, such as from H and CH3.
  • R 12 is as defined herein above, but is not H
  • R 13 is H
  • R 14 is as defined herein above, but is not H
  • R 15 is
  • R 12 and R 14 are as defined herein above, but are not H, and R 13 and R 15 are both H.
  • R A , R B and R c when anyone of R A , R B and R c is phenyl optionally substituted by one or more moieties R 16 , or 5- or 6-membered heterocyclyl optionally substituted by one or more moieties R 16 , said phenyl or heterocyclyl is substituted by 0, 1 , 2 or 3 moieties R 16 , e.g. 0, 1 or 2 moieties R 16 , or 0 or 1 moiety R 16 , e.g. 1 moiety R 16 .
  • R A , R B and R c when anyone of R A , R B and R c is phenyl optionally substituted by one or more moieties R 16 , or 5- or 6-membered heterocyclyl optionally substituted by one or more moieties R 16 , it more particularly is phenyl substituted by 0, 1 , 2 or 3 moieties R 16 , or 0, 1 or 2 moieties R 16 .
  • R A , R B and R c when anyone of R A , R B and R c is phenyl optionally substituted by one or more moieties R 16 , or 5- or 6-membered heterocyclyl optionally substituted by one or more moieties R 16 , it more particularly is 5- or 6-membered heterocyclyl substituted by 0,
  • R A is phenyl optionally substituted by one or more moieties R 16 , or 5- or 6-membered heterocyclyl optionally substituted by one or more moieties R 16 .
  • the compound of formula (I) may be represented by formula (Id) wherein ring B is phenyl or 5- or 6-membered heterocyclyl, k is an integer of from 0 to 3, and Ri6, RB, RC, L and R L are as defined herein.
  • ring B is phenyl
  • the compound of formula (Ic) may be represented by formula (le) wherein k, R 16 , R B , Rc, L and R L are as defined herein.
  • compound in some embodiments of a compound of formula (le), k is 1 and R 16 is in para position, compound may be represented by formula (If)
  • R 16 , R B , Rc, L and R L are as defined herein.
  • R B and R c are both H.
  • any 5- or 6-membered heterocyclyl comprises 1 or more heteroatoms in the ring, e.g. 1 , 2, 3 or 4 heteroatoms.
  • the heterocycyl is aromatic.
  • the heterocyclyl is non-aromatic, and saturated or unsaturated, e.g. the heterocyclyl is non-aromatic and mono-unsaturated.
  • the heterocyclyl may be selected from
  • each moiety R 16 may be independently selected from halogen, cyano, nitro, R17O, C1-C6 alkyl optionally substituted by R17O, C3-C6 cycloalkyl optionally substituted by RI 7 O, R19S, R2oS(0) 2 , R 2 IOC(O), (R 22 ON)C(R 23 ), R 24 R 25 NC(O), R26R27N, R 28 S(O) 2 NR 29 , and R 3 QS(O)2NR 3 IC(O).
  • each R 16 is independently selected from halogen, cyano, nitro, R 17 O, C1-C6 alkyl optionally substituted by R17O, C3-C6 cycloalkyl optionally substituted by RI 7 O, R19S, R2oS(0) 2 , R 2 IOC(O), and R 26 R 27 N.
  • each R 16 is independently selected from halogen, cyano, nitro, RI 7 O, C1-C6 alkyl optionally substituted by RI 7 O, R19S, R 2 oS(0) 2 , R 2 IOC(O), and R 26 R 27 N.
  • each R 16 is independently selected from halogen, cyano, nitro, RnO, C1-C6 alkyl optionally substituted by RI 7 O, R19S, R 2 oS(0) 2 , R 2 IOC(O), and R 26 R 27 N.
  • each R 16 is independently selected from RI 7 O, C1-C6 alkyl optionally substituted by RI 7 O, and C3-C6 cycloalkyl optionally substituted by RI 7 O, e.g. from RI 7 O, C1-C6 alkyl optionally substituted by RI 7 O, in particular from RI 7 O.
  • R 16 when R 16 is C1-C6 alkyl optionally substituted by RI 7 O, it e.g. may be C1-C4 alkyl optionally substituted by RI 7 O, e.g. C1-C3 alkyl optionally substituted by RI 7 O.
  • each R16 is independently selected from F, Cl, cyano, nitro, CH 3 , CF 3 , (CH 3 ) 3 C, CH 3 0, CH 3 S, CH 3 S(O) 2 , COOH, NH 2 , and (CH 3 ) 2 N.
  • R 17 when any R 16 is RI 7 O, C1-C6 alkyl optionally substituted by RI 7 O, or C3-C6 cycloalkyl optionally substituted by RI 7 O, the moiety R 17 may be H, C1-C6 alkyl, or C3-C6 cycloalkyl. In some embodiments, R 17 is selected from H, C1-C4 alkyl, and C3-C4 cycloalkyl, or from H, C1-C3 alkyl and cyclopropyl. In some embodiments, R 17 selected from H and C1 -C6 alkyl, e.g. from H and C1-C4 alkyl, or from H and C1-C3 alkyl, such as from H and CH 3 , in particular H.
  • the moiety R 17 is as defined herein above, but is not H; e.g. R 17 is CH 3 .
  • the moiety R 18 may be H, C1-C6 alkyl, or C3-C6 cycloalkyl.
  • R 18 is selected from H, C1-C4 alkyl, and C3-C4 cycloalkyl, or from H, C1 -C3 alkyl and cyclopropyl.
  • R 18 is selected from H and C1-C6 alkyl, e.g. from H and C1-C4 alkyl, or from H and C1-C3 alkyl, such as from H and CH 3 , in particular H.
  • the moiety R 18 is as defined herein above, but is not H; e.g. R 18 is CH 3 .
  • the moiety R 19 may be H, C1-C6 alkyl, or C3-C6 cycloalkyl.
  • R 19 is selected from H, C1-C4 alkyl, and C3-C4 cycloalkyl, or from H, C1-C3 alkyl and cyclopropyl.
  • R 19 is selected from H and C1-C6 alkyl, e.g. from H and C1-C4 alkyl, or from H and C1-C3 alkyl, such as from H and CH 3 , in particular H.
  • the moiety R 19 is as defined herein above, but is not H; e.g. R 19 is CH 3 .
  • the moiety R 2 o may be H, C1-C6 alkyl, or C3-C6 cycloalkyl.
  • R 20 is selected from H, C1-C4 alkyl, and C3-C4 cycloalkyl, or from H, C1-C3 alkyl and cyclopropyl.
  • R 20 is selected from H and C1 -C6 alkyl, e.g. from H and C1-C4 alkyl, or from H and C1-C3 alkyl, such as from H and CH 3 , in particular H.
  • the moiety R 20 is as defined herein above, but is not H; e.g. R 20 is CH 3 .
  • the moiety R 21 may be H, C1-C6 alkyl, or C3-C6 cycloalkyl.
  • R 21 is selected from H, C1-C4 alkyl, and C3-C4 cycloalkyl, or from H, C1 -C3 alkyl and cyclopropyl.
  • R 21 is selected from H and C1-C6 alkyl, e.g. from H and C1-C4 alkyl, or from H and C1-C3 alkyl, such as from H and CH 3 , in particular H.
  • the moiety R 21 is as defined herein above, but is not H; e.g. R 21 is CH 3 .
  • R 22 when any R 16 is (R 22 ON)C(R 2 3), R 22 may be H, C1-C6 alkyl, or C3-C6 cycloalkyl. In some embodiments, R 22 is selected from H, C1-C4 alkyl, and C3-C4 cycloalkyl, or from H, C1-C3 alkyl and cyclopropyl. In some embodiments, R 22 is selected from H and C1-C6 alkyl, e.g. from H and C1-C4 alkyl, or from H and C1-C3 alkyl, such as from H and CH 3 , in particular H.
  • R 23 is H, C1-C6 alkyl, or C3-C6 cycloalkyl. In some embodiments, R 23 is selected from H, C1-C4 alkyl, and C3-C4 cycloalkyl, or from H, C1-C3 alkyl and cyclopropyl. In some embodiments, R 23 is selected from H and C1-C6 alkyl, e.g. from H and C1-C4 alkyl, or from H and C1-C3 alkyl, such as from H and CH 3 , in particular CH 3 . In some embodiments, the moiety R 23 is as defined herein above, but is not H.
  • R 22 is H and R 23 is as defined herein above, but different from H, e.g. R 23 is CH 3 .
  • each one of R24, R25, R26 and R 2 7 may be independently selected from H, C1-C6 alkyl, and C3-C6 cycloalkyl, e.g. from H, C1-C4 alkyl, and C3-C4 cycloalkyl, or from H, C1-C3 alkyl and cyclopropyl.
  • each one of R24, R25, R26 and R 2 7 is independently selected from H and C1-C6 alkyl, e.g. from H and C1- C4 alkyl, or from H and C1-C3 alkyl, such as from H and CH 3 .
  • each one of R 23 , R29, R30 and R 31 may be independently selected from H, C1-C6 alkyl, and C3-C6 cycloalkyl, e.g. from H, C1-C4 alkyl, and C3-C4 cycloalkyl, or from H, C1-C3 alkyl and cyclopropyl.
  • each one of R 2 8, R29, R30 and R 3 1 is independently selected from H and C1-C6 alkyl, e.g. from H and C1 -C4 alkyl, or from H and C1-C3 alkyl, such as from H and CH 3 .
  • R 2 8 and R 30 are as defined herein above, but are not H, and R29 and R 31 are both H.
  • R A and R c when one of R A and R c , together with R B , forms a divalent group -(CH 2 ) m - wherein m is an integer of from 3 to 5, m e.g. is 3 or 4, in particular 3, e.g. R B and R c may form together a group -(CH 2 )3-.
  • one of R A , R B and R c is H and the other two are independently selected from halogen, cyano, C1-C4 alkyl, RTO, R 2 C(O), R 3 S, and R 4 S(O) 2 ; or, if adjacent, in some embodiments the two other form a biradical -(CH 2 ) m -wherein m is an integer of from 3 to 5.
  • one of R A , R B and R c is H, and the other two are selected from halogen, cyano, C1-C4 alkyl, and RTO, e.g. from halogen, C1-C3 alkyl, and C1-C3 alkoxy, e.g. from F, Cl, methyl and methoxy; or from halogen and C1-C3 alkyl, such as F, Cl, and methyl.
  • one of R A , R B and R c is H and the other two are both selected from halogen, e.g. both are F or Cl, or both are Cl.
  • the two of R A , R B and R c that are different from H are both selected from C1-C3 alkyl and RTO, e.g. both are selected from methyl and methoxy.
  • the two of R A , R B and R c that are different from H are identical with each others, e.g. both are Cl, or both are methyl, or both are RTO, e.g. methoxy.
  • R B and R c are both selected from halogen, cyano, C1-C4 alkyl, and RTO.
  • R B and R c may be both selected from halogen, e.g. both R B and R c are F or Cl, or both R B and R c are Cl.
  • R B and R c are both selected from C1-C4 alkyl and RTO, e.g. both R B and R c are selected from methyl and methoxy, e.g. both are methyl.
  • R B and R c may be different from each other, or may be identical.
  • alkyl either alone or as part of a group, includes straight or branched chain alkyl of the general formula C n H 2n +i-
  • alkenyl refers to a divalent group of formula -(C n H 2n )-.
  • a divalent group of formula -(C n H 2n )- for example, a
  • C2 alkenyl is a moiety of formula -CH 2 CH 2 -, i.e. :
  • C1-C6 alkyl includes any alkyl group having 1, 2, 3, 4, 5 or 6 carbon atoms.
  • C1-C4 alkyl includes methyl, ethyl, n-propyl, isopropyl, n-butyl, secbutyl, isobutyl and tert-butyl.
  • C1-C3 alkyl includes methyl, ethyl, n-propyl and isopropyl.
  • cycloalkyl refers to a cyclic alkyl group of the general formula C n H 2n . i-
  • cycloalkenyl refers to a cyclic alkenyl group of the general formula C n H 2n -3.
  • C3-C6 cycloalkyl refers to cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • phenyl refers to a C 6 H 5 group of the formula
  • heterocyclyl refers to a saturated or unsaturated and aromatic or non-aromatic cyclic moiety containing at least one heteroatom in the ring.
  • heteroaryl refers to an aromatic heterocyclyl, e.g. a pyridyl (also referred to as pyridinyl), tetrazolyl, furyl or pyridiminyl.
  • pyridyl refers to a C 5 NH 5 group of formula including 2-pyridyl, 3 -pyridyl and 4-pyridyl.
  • pyrimidinyl refers to a C 4 N 2 H 4 group of formula including 2-pyrimidinyl, 4-pyrimidinyl and 5-pyrimidinyl.
  • thiazolyl refers to 1 ,2-thiazolyl and 1 ,3-thiazolyl.
  • 1 ,2-thiazolyl refers to a group of formula including 1 ,2-thiazol-3-yl, 1 ,2-thiazoly-4-yl, and 1 ,2-thiazoly-5-yl.
  • 1 ,3-thiazolyl refers to a group of formula including 1 ,3-thiazol-2-yl, 1 ,3-thiazol-4-yl and 1 ,3-thiazol-5-yl.
  • halogen refers to F, Cl, Br and I, preferably F, Cl and Br, more preferably Cl or Br, still more preferably Cl.
  • hydroxy refers to a group of the formula -OH.
  • alkoxy refers to a group of the formula RO, wherein R is alkyl.
  • RO refers to a group of formula
  • RC(O) refers to a moiety of formula
  • the group RS is a group of formula
  • RS(O) 2 refers to a group of formula
  • ROC(O) refers to a group of formula
  • RR'NC(O) refers to a group of formula
  • RS(O) 2 NR' refers to a group of formula
  • RS(O) 2 NR'C(O) refers to a group of formula
  • the compound is not these compounds, each F is
  • R L is not 19 F.
  • the case that R L is 19 F can be also depicted as , wherein the wavy line indicates attachment to the linker L.
  • R L is not 19 F
  • labels which merely comprise 19 F such as e.g. BODIPY, which can be used as a label in the compounds of formula (I) described herein.
  • R A , R B and R c are each independently selected from the group consisting of H, R 14 S(O) 2 NR 15 C(O), phenyl optionally substituted by one or more moieties R 16 , R 5 OC(O), halogen, and C1-C6 alkyl.
  • R 14 S(O) 2 NR 15 C(O) may some of these embodiments, phenyl optionally substituted by one or more moieties R 16 may be phenyl optionally substituted by R17O.
  • phenyl optionally substituted by one or more moieties R 16 may be In some of these embodiments, R 5 OC(O) may some of these embodiments, halogen may be F, Cl, Br or I, preferably F, Cl or Br, more preferably Cl. In some of these embodiments, C1-C6 alkyl may be methyl.
  • R A is H. More preferably, R A is H, R B is H and R c is H.
  • R A is R 14 S(O) 2 NR 15 C(O). More preferably, R A is some of these embodiments, R B may be H, and R c may be H.
  • R A is phenyl optionally substituted by one or more moieties R 16 . More preferably R A is phenyl optionally substituted by R17O. Still more preferably, R A is . In some of these embodiments, R B may be H, and R c may be H.
  • R A is R 5 OC(O). More preferably, some of these embodiments, R B may be H, and R c may be H or halogen, preferably Cl. In some of these embodiments, R B may be H and R c may be halogen, preferably Cl.
  • R B is halogen, more preferably Cl.
  • R A may be H.
  • R c may be, independently, halogen, preferably Cl.
  • R A is H, R B is halogen, and R c is halogen.
  • R A is H, R B is Cl, and R c is Cl.
  • R B is C1-C6 alkyl, more preferably methyl.
  • R A may be H.
  • R c may be, independently, C1- C6 alkyl, preferably methyl.
  • the group L is a linker.
  • Linker Virtually any linker moiety (linker) can be used.
  • the linker may, for example, be a straight or branched hydrocarbon based moiety.
  • the linker can also comprise cyclic moieties. If the linking moiety is a hydrocarbon-based moiety the main chain of the linker may comprise only carbon atoms but can also contain heteroatoms such as oxygen (O), nitrogen (N) or sulfur (S) atoms.
  • the linker may for example include a C1-C20 carbon atom chain or a polyether based chain such as polyethylene glycol based chain with -(O-CH 2 -CH 2 )- repeating units.
  • the linking moiety may comprise between 1 to about 150, 1 to about 100, 1 to about 75, 1 to about 50, or 1 to about 40, or 1 to about 30, or 1 to about 20, including 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, and 19 main chain atoms.
  • the linker L is attached to a carbonyl carbon atom, and to a label R L .
  • the linker L is (L1): (L1), wherein indicates the attachment point to the carbonyl carbon atom;
  • # indicates the attachment point to the label R L .
  • the linker L is (L2): wherein o is an integer ranging from 1 to 6, preferably from 1 to 4, more preferably from 1 to 3, still more preferably o is 1 or 2, even more preferably o is 1; indicates the attachment point to the carbonyl carbon atom; and
  • the linker L is (L2*): (L2*), wherein indicates the attachment point to the carbonyl carbon atom;
  • # indicates the attachment point to the label R L .
  • the linker L is (L3): (L3), wherein: o is an integer ranging from 1 to 6, preferably from 1 to 4, more preferably from 1 to 3, still more preferably o is 1 or 2, even more preferably o is 1; p is an integer ranging from 1 to 6, preferably from 1 to 4, more preferably from 1 to 3, still more preferably p is 2 or 3, even more preferably p is 2;
  • J 5 * indicates the attachment point to the carbonyl carbon atom
  • the linker L is (L3*): wherein indicates the attachment point to the carbonyl carbon atom;
  • # indicates the attachment point to the label R L .
  • the linker L is (L4): wherein
  • R200 is H or C1-C6 alkyl; preferably R 2O o is C1-C6 alkyl, more preferably C1-C3 alkyl, still more preferably methyl or ethyl, even more preferably methyl;
  • R 20 I is H or C1-C6 alkyl; preferably R 20 I is C1-C6 alkyl, more preferably C1-C3 alkyl, still more preferably methyl or ethyl, even more preferably methyl;
  • X is an anion; preferably X is a halogenide, more preferably bromide (Br ); o is an integer ranging from 1 to 15, preferably from 2 to 10, more preferably from 3 to 8, still more preferably from 4 to 6, even more preferably o is 5; p is an integer ranging from 1 to 6, preferably from 1 to 4, more preferably from 1 to 3, still more preferably p is 1 or 2, even more preferably p is 1; q is an integer ranging from 1 to 6, preferably from 1 to 4, more preferably from 1 to 3, still more preferably q is 2 or 3, even more preferably q is 2; indicates the attachment point to the carbonyl carbon atom; and
  • R 200 and R 20 I are the same; preferably R 200 is methyl and R 20 I is methyl. More preferably, the linker L is (L4*): wherein indicates the attachment point to the carbonyl carbon atom; and
  • the linker L is (L5): (L5), wherein
  • R200 is H or C1-C6 alkyl; preferably R 2 oo is C1-C6 alkyl, more preferably C1-C3 alkyl, still more preferably methyl or ethyl, even more preferably methyl; o is an integer ranging from 1 to 15, preferably from 2 to 10, more preferably from 3 to 8, still more preferably from 4 to 6, even more preferably o is 5; indicates the attachment point to the carbonyl carbon atom; and
  • the linker L is (L5*): wherein indicates the attachment point to the carbonyl carbon atom;
  • # indicates the attachment point to the label R L .
  • the linker L is (L6): wherein
  • R 2O O is H or C1-C6 alkyl; preferably R 200 is C1-C6 alkyl, more preferably C1-C3 alkyl, still more preferably methyl or ethyl, even more preferably methyl;
  • R 3O O is H or C1-C6 alkyl; preferably R 300 is C1-C6 alkyl, more preferably C1-C3 alkyl, still more preferably methyl or ethyl, even more preferably methyl;
  • R 30 I is H or C1-C6 alkyl; preferably R 30 I is C1-C6 alkyl, more preferably C1-C3 alkyl, still more preferably methyl or ethyl, even more preferably methyl; o is an integer ranging from 1 to 15, preferably from 2 to 10, more preferably from 3 to 8, still more preferably from 4 to 6, even more preferably o is 5; p is an integer ranging from 1 to 6, preferably from 1 to 4, more preferably from 1 to 3, still more preferably o is 2 or 3, even more preferably p is 2; indicates the attachment point to the carbonyl carbon atom; and
  • R 2O o, R 300 and R 30 I are the same; preferably R 2 oo is methyl, R 300 is methyl and R 30 I is methyl. More preferably, the linker L is (L6*): wherein indicates the attachment point to the carbonyl carbon atom; and
  • # indicates the attachment point to the label R L .
  • the linker L is (L7): wherein
  • R200 is H or C1-C6 alkyl; preferably R 2 oo is C1-C6 alkyl, more preferably C1-C3 alkyl, still more preferably methyl or ethyl, even more preferably methyl;
  • R201 is H or C1-C6 alkyl; preferably R201 is C1-C6 alkyl, more preferably C1-C3 alkyl, still more preferably methyl or ethyl, even more preferably methyl; o is an integer ranging from 1 to 15, preferably from 2 to 10, more preferably from 3 to 8, still more preferably from 4 to 6, even more preferably o is 5; indicates the attachment point to the carbonyl carbon atom; and
  • R 2 oo and R201 are the same; preferably R 2 oo is methyl and R201 is methyl. More preferably, the linker L is (L7*): wherein indicates the attachment point to the carbonyl carbon atom; and
  • # indicates the attachment point to the label R L .
  • the linker L is (L8): wherein
  • R200 is H or C1-C6 alkyl; preferably R 2 oo is C1-C6 alkyl, more preferably C1-C3 alkyl, still more preferably methyl or ethyl, even more preferably methyl;
  • R201 is H or C1-C6 alkyl; preferably R201 is C1-C6 alkyl, more preferably C1-C3 alkyl, still more preferably methyl or ethyl, even more preferably methyl;
  • R 3 oo is H or C1-C6 alkyl; preferably R 300 is C1-C6 alkyl, more preferably C1-C3 alkyl, still more preferably methyl or ethyl, even more preferably methyl;
  • R301 is H or C1-C6 alkyl; preferably R 30 I is C1-C6 alkyl, more preferably C1-C3 alkyl, still more preferably methyl or ethyl, even more preferably methyl; o is an integer ranging from 1 to 15, preferably from 2 to 10, more preferably from 3 to 8, still more preferably from 4 to 6, even more preferably o is 5; p is an integer ranging from 1 to 6, preferably from 1 to 4, more preferably from 1 to 3, still more preferably o is 2 or 3, even more preferably p is 2; indicates the attachment point to the carbonyl carbon atom; and
  • R 2O o, R201, R300 and R301 are the same; preferably R 2 oo is methyl, R 20 I is methyl, R 300 is methyl and R 30 I is methyl. More preferably, the linker L is (L8*): wherein indicates the attachment point to the carbonyl carbon atom; and
  • # indicates the attachment point to the label R L .
  • the linker L is (L9): wherein o is an integer ranging from 1 to 6, preferably from 1 to 4, more preferably from 1 to 3, still more preferably o is 1 or 2, even more preferably o is 1 ; p is an integer ranging from 1 to 10, preferably from 1 to 8, more preferably from 2 to 5, still more preferably p is 3 or 4, even more preferably p is 3; q is an integer ranging from 1 to 5, preferably from 1 to 3; indicates the attachment point to the carbonyl carbon atom; and
  • the linker L is (L9*): wherein q is an integer ranging from 1 to 3; indicates the attachment point to the carbonyl carbon atom; and
  • # indicates the attachment point to the label R L .
  • the linker L is (L10): (L10), wherein o is an integer ranging from 1 to 6, preferably from 1 to 4, more preferably from 1 to 3, still more preferably o is 1 or 2, even more preferably o is 1; p is an integer ranging from 1 to 10, preferably from 1 to 8, more preferably from 2 to 5, still more preferably p is 3 or 4, even more preferably p is 3; indicates the attachment point to the carbonyl carbon atom; and
  • the linker L is (L10*): wherein indicates the attachment point to the carbonyl carbon atom;
  • the linker L is (L11): wherein o is an integer ranging from 1 to 6, preferably from 1 to 4, more preferably from 1 to 3, still more preferably o is 1 or 2, even more preferably o is 1; p is an integer ranging from 1 to 10, preferably from 2 to 8, more preferably from 2 to 6, still more preferably p is 2 or 4, even more preferably p is 3; indicates the attachment point to the carbonyl carbon atom; and
  • the linker L is (L11*): (L11*), wherein indicates the attachment point to the carbonyl carbon atom;
  • # indicates the attachment point to the label R L .
  • the linker L is (L12): wherein o is an integer ranging from 1 to 20, preferably from 2 to 15, more preferably from 3 to 10, still more preferably from 4 to 6, even more preferably o is 5;
  • R 2 OO is H or C1-C6 alkyl; preferably R 2O o is H; indicates the attachment point to the carbonyl carbon atom; and
  • R 200 is C1-C3 alkyl, preferably methyl or ethyl, more preferably methyl. Still more preferably, R 200 is H. Even more preferably, the linker L is (L12*): (L12*), wherein indicates the attachment point to the carbonyl carbon atom; and
  • # indicates the attachment point to the label R L .
  • the group R L is a label.
  • label in general refers to a moiety that allows detection and/or imaging.
  • the label is not particularly limited and may include, for example, labels suitable for use in molecular imaging techniques.
  • the label may be a label suitable for single photon emission tomography (SPECT), positron emission tomography (PET), optical imaging, ultrasound and/or photoacoustic imaging.
  • SPECT single photon emission tomography
  • PET positron emission tomography
  • optical imaging ultrasound and/or photoacoustic imaging.
  • the term “label” can also be replaced by the term “tracer”.
  • any suitable known label modality for use with any suitable imaging or detection method as described herein, are possible.
  • any suitable label moiety known to the person of skill in the art for use in optical imaging may include a fluorescent label such as Cy5.5®, Cy3®, Cy3.5®, Cy5®, or Cy7®)
  • PET non-limiting examples may include a label having a 18 F group
  • SPECT non-limiting examples may include a label having a 123 l, 124 l, 125 l, " m Tc, 186 Re or 188 Re group
  • photoacoustic imaging may include an absorber such as polymethine dyes (non-limiting examples include cyanine dyes), phthalocyanines, or naphthalocyanines) may be used.
  • suitable labels for optical imaging may include dyes such as, for example, fluorescein isothiocyanate (FITC), 1 ,T-dioctadecyl-3,3,3',3'-tetramethyl indotricarbocyanine iodide (DiR), a coumarin dye, a rhodamine dye, a carbopyronin dye, an oxazine dye, a fluorescein dye, a cyanine dye, a boron-dipyrromethene (BODIPY) dye, a squaraine dye, and a squaraine rotaxane dye.
  • FITC fluorescein isothiocyanate
  • DiR 1 ,T-dioctadecyl-3,3,3',3'-tetramethyl indotricarbocyanine iodide
  • LiR fluorescein isothiocyanate
  • LiR 1 ,
  • Coumarin dyes, rhodamine dyes, carbopyronin dyes and oxazine dyes are, for example, commercially available under the trade name ATTO® from ATTO-TEC GmbH.
  • coumarin dyes, rhodamin dyes, fluorescein dyes and cyanine dyes are, for example, commercially available under the trade name Alexa Fluor® from Molecular Probes, Inc.
  • Coumarin dyes, rhodamin dyes, fluorescein dyes and cyanine dyes are, for example, also commercially available under the trade name DyLight® Fluor from Dyomics in collaboration with Thermo Fisher Scientific, Inc.
  • suitable labels for MRI may include a perfluorinated 19 F label and Gd(DOTA), wherein DOTA denotes 1 ,4,7,10- tetraazacyclododecane-1 ,4,7,10-tetraacetic acetic acid and any conjugated base thereof.
  • suitable labels for ultrasound imaging may include gas filled microbubbles which are stabilized by a shell, wherein the shell may, for example, be comprised of proteins, lipids or polymers.
  • Suitable labels for SPECT may include an 123 l, 124 l, 125 l and/or " m Tc.
  • Nonlimiting examples may include:
  • each R 9 is independently selected from the group consisting of -CH 3 , preferably wherein each R 9 is the same.
  • R 9 is methyl.
  • the SPECT label is negatively or positively charged, preferably negatively charged.
  • Suitable labels for PET may include an 18 F or a 68 Ga.
  • Non limiting examples may include :
  • the PET label contains an acidic group, preferably a sulfonic acid group.
  • Labels for optical imaging may include any suitable fluorophore or dye known in the art.
  • Non-limiting examples may include a cyanine dye such as cyanine 3, cyanine 3.5, cyanine 5, cyanine 5.5 and cyanine 7 or related analogues.
  • a cyanine dye such as cyanine 3, cyanine 3.5, cyanine 5, cyanine 5.5 and cyanine 7 or related analogues.
  • the commercially available Cy3®, Cy3.5®, Cy5®, Cy5.5®, Cy7® dyes provided by GE Healthcare may be used.
  • fluorophores may include 7-amino-4-methylcoumarin (AMC), fluorescein isothiocyanate (FITC), fluorescein carboxylic acid, 5-carboxytetramethylrhodamine (TAMRA), indocyanine green, a DyLight® Fluor dye, an ATTO® dye, a BODIPY® dye, a SETA® dye, a SeTau® dye, an Alexa Fluor® dye from Invitrogen, an IRdye® dye from Li-COR Bioscience, an SRfluor® dye from Molecular Targeting Technologies, a HyLyteTM Fluor dye from Anaspec, CFTM633 from Biotium, and an indotricarbocyanine (ITCC) dye.
  • AMC 7-amino-4-methylcoumarin
  • FITC fluorescein isothiocyanate
  • TAMRA 5-carboxytetramethylrhodamine
  • indocyanine green a DyLight®
  • the label R L is a metal binding group with a metal coordinated by said binding group.
  • the label R L may be a metal binding group for a metal selected from " m Tc, 186 Re, 188 Re, 111 In, 67 Ga, 68 Ga, 64 Cu and/or 89 Zr.
  • the metal binding group for the metal can be any group which is able to coordinate to the metal like " m Tc, 186 Re, 188 Re, 111 1 n, 67 Ga, 68 Ga, 64 Cu and/or 89 Zr and at the same time bound covalently to L of formula (I).
  • the binding group is a monodentate, bidentate, tridentate or polydentate binding group able to coordinate the metal at one, two, three or several coordination sites of said metal. In some embodiments the binding group is negatively or positively charged.
  • the metal binding group may coordinate said metal together with an additional binding group. Accordingly, in some embodiments the binding group coordinates the metal together with an additional metal binding group, wherein the additional binding group is preferably not bound to the compound according to formula (I).
  • the additional binding group is a monodentate, bidentate, tridentate or polydentate binding group able to coordinate the metal at one, two, three or several coordination sites of said metal, preferably a bidentate binding group, more preferably bathophenanthrolinedisulfonic acid disodium salt hydrate.
  • the binding group is negatively or positively charged, preferably negatively charged.
  • the binding group and the metal or the binding group, the additional binding group and the metal are a SPECT label.
  • the label R L is a positron emission tomography (PET) label.
  • the label R L is a single photon emission tomography (SPECT) label.
  • the label R L is an optical imaging label. In some embodiments, the label R L is a magnetic resonance imaging (MRI) label. In some embodiments, the label R L is an ultrasound label. In some embodiments, the label R L is a photoacoustic label. In some embodiments, the label RL comprises a group selected from the group consisting of 18 F, 68 Ga, 123 l, 124 l, 125 l, " m Tc, 111 ln, 67 Ga, 64 Cu, 11 C, 89 Zr, fluorescent dyes, phosphorescent dyes, and photoacoustic absorbers.
  • the label R L is a positron emission tomography (PET) label.
  • the label R L is 18 F.
  • the case that the label R L — 18 F is 18 F can be also depicted as , wherein the wavy line indicates attachment to the linker L.
  • the 18 F labelled compound may be present in a mixture with a compound having 19 F at the position of the 18 F.
  • the ratio of the 18 F compound to the 19 F compound may be about 1 to 10.
  • the linker L is selected from the group consisting of (L1), (L3), (L3*), (L4), (L4*), (L5), (L5*), (L6), (L6*), (L7), (L7*), (L8) and (L8*), wherein (L1), (L3), (L3*), (L4), (L4*), (L5), (L5*), (L6), (L6*), (L7), (L7*), (L8) and (L8*) are as defined herein. Accordingly, when the label is 18 F, the linker may be (L1), wherein (L1) is as defined herein.
  • the linker may be (L3), wherein (L3) is as defined herein.
  • the linker may be (L3*), wherein (L3*) is as defined herein.
  • the linker may be (L4), wherein (L4) is as defined herein.
  • the linker may be (L4*), wherein (L4*) is as defined herein.
  • the linker may be (L5), wherein (L5) is as defined herein.
  • the linker may be (L5*), wherein (L5*) is as defined herein.
  • the linker may be (L6), wherein (L6) is as defined herein.
  • the linker When the label is 18 F, the linker may be (L6*), wherein (L6*) is as defined herein.
  • the linker When the label is 18 F, the linker may be (L7), wherein (L7) is as defined herein.
  • the linker When the label is 18 F, the linker may be (L7*), wherein (L7*) is as defined herein.
  • the linker may be (L8), wherein (L8) is as defined herein.
  • the linker When the label is 18 F, the linker may be (L8*), wherein (L8*) is as defined herein.
  • the compound of formula (I) may be:
  • the compound of formula (I) may be: or a salt, isomer, or tautomer thereof.
  • the compound of formula (I) may be:
  • the label R L is: wherein * indicates the attachment point to the linker L.
  • the linker L may be (L9), wherein (L9) is as defined herein.
  • the linker L may be (L9*), wherein (L9*) is as defined herein.
  • the label R L is: wherein * indicates the attachment point to the linker L.
  • the linker L may be (L9), wherein (L9) is as defined herein.
  • the linker L may be (L9*), wherein (L9*) is as defined herein.
  • the label R L is: wherein * indicates the attachment point to the linker L.
  • the linker L may be (L9), wherein (L9) is as defined herein.
  • the linker L may be (L9*), wherein (L9*) is as defined herein.
  • the compound of formula (I) may be: or a salt, isomer, or tautomer thereof.
  • the compound of formula (I) may be:
  • the compound of formula (I) may be: or a salt, isomer, or tautomer thereof.
  • the label R L is a single photon emission tomography (SPECT) label.
  • SPECT single photon emission tomography
  • the label R L is: wherein * indicates the attachment point to the linker L.
  • the linker L may be (L10), wherein (L10) is as defined herein.
  • the linker L may be (L10*), wherein (L10*) is as defined herein.
  • the compound of formula (I) may be: or a salt, isomer, or tautomer thereof.
  • the label R L is:
  • the linker L may be (L2), wherein (L2) is as defined herein. In some of these embodiments, the linker L may be (L2*), wherein (L2*) is as defined herein.
  • the label R L is: wherein * indicates the attachment point to the linker L.
  • the linker L may be (L2), wherein (L2) is as defined herein.
  • the linker L may be (L2*), wherein (L2*) is as defined herein.
  • the compound of formula (I) may be:
  • the compound of formula (I) may be: or a salt, isomer, or tautomer thereof.
  • the label R L may be or may comprise a photoacoustic imaging label.
  • the photoacoustic label is a phthalocyanine.
  • the photoacoustic label is a naphthalocyanine.
  • the photoacoustic label is a polymethine dye.
  • the label R L may comprise or may be an optical imaging label.
  • the optical imaging label is a dye.
  • the dye is fluorescein isothiocyanate (FITC).
  • the dye is 1 ,T-dioctadecyl-3,3,3',3'-tetramethyl indotricarbocyanine iodide (DiR).
  • the dye is a coumarin dye.
  • the dye is a rhodamine dye.
  • the dye is a carbopyronin dye.
  • the dye is an oxazine dye.
  • the dye is a fluorescein dye.
  • the dye is a cyanine dye.
  • the dye is a boron-dipyrromethene (BODIPY) dye.
  • the dye is a squaraine dye.
  • the dye is a squaraine rotaxane dye. In some embodiments the dye is an Alexa Fluor® dye. In some embodiments the dye is a DyLight® Fluor dye. In some embodiments the dye is an ATTO® dye. In some embodiments the dye is a BODIPY® dye. In some embodiments the dye is a SETA® dye. In some embodiments the dye is a SeTau® dye. In some embodiments the dye is Alexa Fluor® 488.
  • the optical imaging label is a fluorophore.
  • the fluorophore is a polymethine dye.
  • the polymethine dye is a cyanine dye.
  • the cyanine dye is cyanine 3.
  • the cyanine dye is cyanine 3.5.
  • the cyanine dye is cyanine 5.
  • the cyanine dye is cyanine 5.5.
  • the cyanine dye is cyanine 7.
  • the label R L is:
  • the linker L may be (L11), wherein (L11) is as defined herein. In some of these embodiments, the linker L may be (L11*), wherein (L11*) is as defined herein.
  • the label R L is: wherein * indicates the attachment point to the linker L.
  • the linker L may be (L11), wherein (L11) is as defined herein. In some of these embodiments, the linker L may be (L11*), wherein (L11*) is as defined herein. [00210] In some embodiments, the label R L is: wherein * indicates the attachment point to the linker L. In some of these embodiments, the linker L may be (L11), wherein (L11) is as defined herein. In some of these embodiments, the linker L may be (L11*), wherein (L11*) is as defined herein.
  • the label R L is: wherein * indicates the attachment point to the linker L.
  • the linker L may be (L11), wherein (L11) is as defined herein.
  • the linker L may be (L11*), wherein (L11*) is as defined herein.
  • the compound of formula (I) may be: or a salt, isomer, or tautomer thereof.
  • the compound of formula (I) may be: or a salt, isomer, or tautomer thereof.
  • the compound of formula (I) may be: or a salt, isomer, or tautomer thereof.
  • the compound of formula (I) may be: or a salt, isomer, or tautomer thereof.
  • the label R L is: wherein * indicates the attachment point to the linker L.
  • the linker L may be (L11), wherein (L11) is as defined herein.
  • the linker L may be (L11*), wherein (L11*) is as defined herein.
  • the linker L may be (L12), wherein (L12) is as defined herein.
  • the linker L may be (L12*), wherein (L12*) is as defined herein.
  • the compound of formula (I) may be: or a salt, isomer, or tautomer thereof.
  • Compounds of the invention may also include the following.
  • the compounds disclosed herein are diagnostic compounds.
  • the present invention further relates to a diagnostic composition
  • a diagnostic composition comprising any of the compounds as described herein above and a pharmaceutically or diagnostically acceptable excipient.
  • the present invention provides the use of any of the compounds as disclosed herein above in a method of diagnosis.
  • the diagnosis is a diagnosis of an inflammatory disease in a subject.
  • the method of diagnosing an inflammatory disease is a non-invasive molecular imaging method.
  • the non-invasive molecular imaging method is an in vivo molecular imaging method.
  • the non-invasive molecular imaging method is an in vitro molecular imaging method.
  • the non-invasive molecular imaging method is single photon emission tomography (SPECT).
  • SPECT single photon emission tomography
  • PET positron emission tomography
  • the non-invasive molecular imaging method is optical imaging. In some embodiments the non-invasive molecular imaging method is magnetic resonance imaging (MRI). In some embodiments the non-invasive molecular imaging method is ultrasound. In some embodiments the non-invasive molecular imaging method is photoacoustic imaging.
  • the inflammatory disease is associated with phagocyte and/or epithelial cell activation in said subject. In some embodiments the inflammatory disease is further associated with an overexpression and accumulation of S100A9 in said subject. In some embodiments the inflammatory disease is dermatitis, preferably irritant dermatitis (ICD). In some embodiments the inflammatory disease is atherosclerosis. In some embodiments the inflammatory disease is psoriasis. In some embodiments the inflammatory disease is an autoimmune disease. In some embodiments the inflammatory disease is arthritis. In some embodiments the inflammatory disease is allergies. In some embodiments the inflammatory disease is cardiovascular processes. In some embodiments the inflammatory disease is local and systemic infections. In some embodiments the inflammatory disease is a neuroinflammatory disease. In some embodiments the inflammatory disease is acute lung injury (ALI). In some embodiments the inflammatory disease is a tumor.
  • ICD irritant dermatitis
  • the method of diagnosis as described herein is typically a method of an early stage diagnosis.
  • the inflammatory disease diagnosed by the method of the present invention is at local site.
  • the subject of the present invention is typically a mammal.
  • the mammal is a mouse.
  • the mammal is a rat.
  • the mammal is a guinea pig.
  • the mammal is a rabbit.
  • the mammal is a cat.
  • the mammal is a dog.
  • the mammal is a horse.
  • the mammal is human.
  • the method of the present invention comprises administering any of the compounds as disclosed herein above to the subject.
  • the administration of the compound may be carried out variously. In some embodiments the administration is carried out intravenously. In some embodiments the administration is carried out subcutaneously. In some embodiments the administration is carried out intralesionally. In some embodiments the administration is carried out by application to mucous membranes. In some embodiments the administration is carried out orally. In some embodiments the administration is carried out parenterally. In some embodiments the administration is carried out intramuscularly. In some embodiments the administration is carried out intraperitoneally. In some embodiments the administration is carried out by intranasal instillation. In some embodiments the administration is carried out by implantation.
  • the administration is carried out by intracavitary instillation. In some embodiments the administration is carried out by intravesical instillation. In some embodiments the administration is carried out intraocularly. In some embodiments the administration is carried out intraarterially. In some embodiments the administration is carried out transdermally. Preferably, the administration is carried out intravenously, subcutaneously, intralesionally, or by application to mucous membranes.
  • the present invention relates to a method of diagnosing an inflammatory disease in a subject, comprising: a) administering to said subject any of the compounds as disclosed herein above, b) detecting the administered compound using an in vivo non-invasive molecular imaging technique, thereby collecting imaging data, c) comparing the imaging data received in step b) to reference imaging data.
  • the present invention provides a non-invasive method of detecting or imaging accumulation of S100A9 in the body of a subject to whom any of the compounds as disclosed herein above has been pre-delivered, comprising: a) detecting the administered compound using an in vivo non-invasive molecular imaging technique, thereby collecting imaging data, b) comparing the imaging data received in step a) to reference imaging data.
  • an increased signal in the imaging data from the subject as compared to reference imaging data indicates the presence of an inflammatory disease in said subject, wherein no difference in the signal in the imaging data from the subject as compared to reference imaging data indicates no presence of an inflammatory disease in said subject.
  • the present invention relates to the use of any of the compounds as disclosed herein above for the preparation of a diagnostic composition for diagnosing an inflammatory disease associated with phagocyte and/or epithelial cell activation in a subject.
  • the present invention also provides a method for evaluating whether a subject may be at risk of developing an inflammatory disease associated with phagocyte and/or epithelial cell activation, the method comprising: a) administering to said subject any of the compounds as disclosed herein above, b) detecting the administered compound using an in vivo non-invasive molecular imaging technique, thereby collecting imaging data, c) comparing the imaging data received in step b) to reference imaging data.
  • a significantly increased signal in the imaging data from the subject as compared to reference imaging data indicates that said subject is at higher risk of developing an inflammatory disease associated with phagocyte and/or epithelial cell activation.
  • a signal in the imaging data at a normal level as compared to reference imaging data indicates that said subject is at lower risk of developing an inflammatory disease associated with phagocyte and/or epithelial cell activation.
  • a method of monitoring or evaluating the progression of an inflammatory disease associated with phagocyte and/or epithelial cell activation in a patient comprising: a) administering to said subject any of the compounds as disclosed herein above, b) detecting the administered compound using an in vivo non-invasive molecular imaging technique, thereby collecting imaging data, c) comparing the imaging data received in step b) to reference imaging data obtained from said patient at an earlier date, wherein the result of the comparison of c) provides an evaluation of the progression of the inflammatory disease associated with phagocyte and/or endothelial cell activation in said patient.
  • a significantly increased signal in the imaging data from the patient as compared to reference imaging data obtained from said patient at an earlier date indicates a progression of the inflammatory disease associated with phagocyte and/or endothelial cell activation in said patient.
  • no change in the signal of the imaging data from the patient or a decreased signal in the imaging data from the patient as compared to reference imaging data obtained from said patient at an earlier date indicates no progression or a regression of the inflammatory disease associated with phagocyte and/or endothelial cell activation in said patient.
  • the present invention provides a method of imaging an inflammatory disease in a subject, comprising: a) administering to said subject any of the compounds as disclosed herein above, b) detecting the administered compound using an in vivo non-invasive molecular imaging method, thereby collecting imaging data.
  • an in vitro method of diagnosing an inflammatory disease in a subject to whom any of the compounds as disclosed herein above has been pre-delivered comprising: a) analyzing a sample taken from said subject, b) detecting said pre-delivered compound using a non-invasive molecular imaging method, thereby collecting imaging data, c) comparing the imaging data received in step b) to reference imaging data.
  • an increased signal in the imaging data from the subject as compared to reference imaging data indicates the presence of an inflammatory disease in said subject, wherein no difference in the imaging signal in the imaging data from the subject as compared to reference imaging data indicates no presence of an inflammatory disease in said subject.
  • the imaging data of the present invention underline the applicability of the compounds of formula (I) comprising a label in the diagnosis of inflammatory and cardiovascular diseases associated with S100A9 overexpression and accumulation at local site of inflammation.
  • the present invention provides the use of any of the compounds of formula (I) comprising a label as disclosed herein for use in a method of diagnosis, wherein the diagnosis is typically a diagnosis of an inflammatory disease.
  • diagnosis or “diagnosis” when used herein means determining or detecting if a subject suffers from an inflammatory disease or disorder.
  • diagnosis of an inflammatory disease
  • the methods of diagnosis disclosed herein may also be employed as methods of providing indications useful in the diagnosis of an inflammatory disease.
  • the inflammatory disease or disorder as described herein is associated with phagocyte and/or epithelial cell activation in said subject. This activation is accompanied by an increased expression and secretion of S100A9 by said cells, which binds to both the extracellular matrix and receptors such as TLR4 or RAGE on the immune cell surface, thereby amplifying inflammatory reactions.
  • the inflammatory disease or disorder of the present invention is further associated with an overexpression and accumulation of S100A9 in said subject.
  • the term “overexpression” is used herein to mean above the normal expression level of S100A9 protein in a particular tissue or at a local stage in said subject.
  • accumulation when used herein refers to the enrichment of the overexpressed S100A9 protein in a particular tissue or at a local stage in said subject.
  • the inflammatory disease is at local site of the inflammation.
  • “At local site” when used herein means that S100A9 can be visualized in vivo at spatially limited areas in the tissue of a subject whereas biomarkers measured in the blood only reflect the systemic states, which is however strongly affected by factors like metabolism or blood clearance, limiting the specificity and sensitivity of these approaches. Accordingly, the compounds of the present invention in combination with the imaging techniques described elsewhere herein allow for the reliable detection of S100A9 when locally expressed during an inflammatory disease.
  • the inflammatory disease can be diagnosed at an early stage of inflammation.
  • the term “early stage” as used herein encompasses, but is not limited to medical conditions in which the afflicted subject, e.g. the afflicted human subject, shows little to no perceptible exterior sign or symptoms of inflammation and the overall physical condition of said subject is apparently preserved, although some accumulation of S100A9 may be evident.
  • Exterior signs or symptoms of inflammation include, but are not limited to classical signs of inflammation such as pain, heat, redness, rash, swelling, skin lesions or fever, which however are strongly dependent on the type of inflammatory disease and the place of occurrence in the body.
  • disease refers to any physical state of a subject connected with incorrectly functioning organ, part, structure, or system of the body resulting from the effect of genetic or developmental errors, infection, poisons, nutritional deficiency or imbalance, toxicity, or unfavorable environmental factors, illness, sickness, or ailment.
  • disease or “disorder” further includes any impairment of the normal physical state of the subject or one of its parts that interrupts or modifies the performance of vital functions that are typically manifested by distinguishing signs and symptoms.
  • inflammation refers to a part of complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants.
  • inflammation is a protective response involving host cells, blood vessels, and proteins and other mediators that is intended to eliminate the initial cause of cell injury, as well as the necrotic cells and tissues resulting from the original insult, and to initiate the process of repair.
  • the inflammation described herein can be generally classified as either acute or chronic.
  • the acute inflammation is the initial response of the body to harmful stimuli and is achieved by the increased movement of plasma and leukocytes (especially granulocytes) from the blood into the injured tissues, involving the local vascular system, the immune system, and various cells within the injured tissue.
  • Prolonged inflammation also known as chronic inflammation, leads to a progressive shift in the type of cells present at the site of inflammation and is characterized by simultaneous destruction and healing of the tissue from the inflammatory process.
  • the term “Inflammatory diseases” or “inflammatory disorder” when used herein refer to any physical state of the subject of the present invention which is related to a disease or a physical reaction connected with the occurrence of inflammation in said subject.
  • the inflammatory disease or disorder of the present invention is preferably related to an increased phagocyte and/or epithelial cell activation and a S100A9 overexpression and accumulation in said subject.
  • inflammatory and cardiovascular diseases or disorders are known as to be associated with an increased phagocyte and/or epithelial cell activation and are within the scope of the present invention. Since these cells express and locally secrete high levels of the S100 protein complex S100A8/S100A9 which acts as so called alarmin or Danger Associated Molecular Pattern (DAMP) molecule with potent pro-inflammatory capacities, many inflammatory and cardiovascular diseases are associated with an overexpression and accumulation of S100A9 (Vogl et al. 2007, Loser et al. 2010, Chan et al. 2012).
  • the inflammatory disease of the present invention is dermatitis.
  • the inflammatory disease is atherosclerosis.
  • the inflammatory disease is psoriasis. In some embodiments the inflammatory disease is an autoimmune disease. In some embodiments the inflammatory disease is arthritis. In some embodiments the inflammatory disease is allergies. In some embodiments the inflammatory disease is cardiovascular processes. In some embodiments the inflammatory disease is local and systemic infections. In some embodiments the inflammatory disease is a neuroinflammatory disease. In some embodiments the inflammatory disease is acute lung injury (ALI). In some embodiments the inflammatory disease is a tumor.
  • ALI acute lung injury
  • a subject when used herein includes mammalian and non-mammalian subjects.
  • the subject of the present invention is a mammal, including human, domestic and farm animals, nonhuman primates, and any other animal that has mammary tissue.
  • the mammal is a mouse.
  • the mammal is a rat.
  • the mammal is a guinea pig.
  • the mammal is a rabbit.
  • the mammal is a cat.
  • the mammal is a dog.
  • the mammal is a monkey.
  • the mammal is a horse.
  • the mammal of the present invention is a human.
  • a subject also includes human and veterinary patients.
  • the present invention provides a method of diagnosing an inflammatory disease in a subject, comprises (a) administering to said subject any of the labelled compounds of formula (I) described herein above, (b) detecting the administered compounds using in vivo non-invasive molecular imaging techniques, thereby collecting imaging data, and (c) comparing the imaging data received in step (b) to reference imaging data.
  • the method of diagnosing comprises an active administration of any of the compounds according to the present invention to a subject.
  • the administration of the compound may be carried out variously.
  • the compounds as disclosed herein above are administered intravenously.
  • the administration of the compound is carried out orally.
  • the administration is carried out parenterally.
  • the administration is carried out subcutaneously. In some embodiments the administration is carried out intramuscularly. In some embodiments the administration is carried out intraperitoneally. In some embodiments the administration is carried out by intranasal instillation. In some embodiments the administration is carried out by implantation. In some embodiments the administration is carried out by intracavitary instillation. In some embodiments the administration is carried out by intravesical instillation. In some embodiments the administration is carried out intraocularly. In some embodiments the administration is carried out intraarterially. In some embodiments the administration is carried out intralesionally. In some embodiments the administration is carried out transdermally. In some embodiments the administration is carried out by application to mucous membranes.
  • the administration is carried out intravenously, subcutaneously, intralesionally, or by application to mucous membranes.
  • the use of any of the compounds according to the present invention in a method of diagnosis comprises administering said compound to the subject.
  • the present invention further provides a non- invasive method of detecting or imaging accumulation of S100A9 in the body of a subject to whom any of the labeled compounds described herein above has been pre-delivered, comprising (a) detecting the administered compound using an in vivo non-invasive molecular imaging technique, thereby collecting imaging data, and (b) comparing the imaging data received in step (a) to reference imaging data.
  • the method of detecting or imaging S100A9 in the body of a subject does not comprise an active administration of any of the compounds according to the present invention, but refers to a situation, where any of the compounds according to the present invention has been pre-delivered to said subject.
  • Pre-delivered includes in this regard, that the compounds comprising a label have been delivered to the subject prior to the methods and uses of the present invention (and all associated embodiments), i.e. before the methods of the invention are to be carried out.
  • the term “detecting” when used herein refers to the visualization and the qualitative analysis of the presence or absence of S100A9 in vivo using the compounds of the present invention and any of the molecular imaging techniques described elsewhere herein.
  • the signal in the imaging data received from the subject during the detection step as described in various aspects of the present invention can be considered as the reflected signal received from the label of the administered compound of formula (I) comprising a label.
  • the method when comparing the collected imaging data to reference imaging data, the method equally comprises comparing the signal received from the label of the administered compound to a detected reference signal.
  • the reference imaging data or the detected reference signal typically derives from a reference subject, which is a healthy subject to whom the same labelled compound of the present invention has been delivered.
  • the term “healthy subject” when used herein refers to a subject not suffering from an inflammatory disease or disorder associated with phagocyte and/or epithelial cell activation and overexpression and accumulation of S100A9.
  • the collected imaging data of the subject as described herein indicate the level of S100A9 in said subject
  • the reference imaging data indicate the level of S100A9 in the reference subject. Accordingly, an increased signal in the imaging data from the subject as compared to reference imaging data indicates the presence of an inflammatory disease in said subject. Alternatively, no difference in the signal in the imaging data from the subject as compared to reference imaging data indicates no presence of an inflammatory disease in said subject.
  • an injectable imaging agent is required to visualize biological processes non-invasively in vivo and to be able to do quantifications.
  • compounds of formula (I) comprising a label can be applied to visualize inflammatory processes associated with an increased accumulation of S100A9 at local site, using non- invasive molecular imaging techniques to collect imaging data.
  • These compounds comprise a label, which can be detected highly sensitive and a ligand exhibiting high affinity towards the desired target.
  • Non-invasive as used herein means that no break in the skin of a subject is created, for example, an incision, and there is no contact with the mucosa, or skin break, or internal body cavity beyond a natural or artificial body orifice.
  • the compounds of the present invention are well suited to detect molecular level of S100A9 at local site of inflammation when applying various molecular imaging techniques.
  • imaging techniques such as SPECT labels, PET labels, optical imaging labels, ultrasound labels or photoacoustic labels
  • the compounds of the present invention are well suited to detect molecular level of S100A9 at local site of inflammation when applying various molecular imaging techniques.
  • the combination of known imaging techniques and the compounds of formula (I) comprising a label allow for the necessary cellular and molecular specificity and sensitivity to detect inflammatory disease activity itself, and image S100A9 at molecular level in inflammatory disease models.
  • Various aspects of the present invention comprise the detection of labelled compounds using different non-invasive molecular imaging techniques.
  • In vivo optical molecular imaging is typically performed on small animals to study the physiologic, pathologic or pharmacologic effects of various drugs or diseases.
  • Molecular imaging can also be performed on humans, and the present invention underlines that molecular imaging provides substantial advances in diagnostic imaging.
  • the benefits of in vivo imaging of small animals are significant because it allows processes and responses to be visualized in realtime in their native environments, and allows longitudinal studies to be performed using the same small animal over time, allowing evaluation of disease progression or response to treatment. Further, in vivo imaging of small animals reduces the number of animals required for a study, and can reduce the variance in studies where disease manifestation varies from animal to animal.
  • the compounds of the present invention comprise a single photon emission tomography (SPECT) label, e.g. labels comprising " m Tc, 123 l, or 125 l, as described elsewhere herein.
  • SPECT single photon emission tomography
  • These labels particularly allow for the application of said compounds in SPECT imaging, a nuclear medicine tomographic imaging technique using gamma rays.
  • SPECT is very similar to conventional nuclear medicine planar imaging using a gamma camera, but is also able to provide true 3D information. This information is typically presented as cross-sectional slices through the patient, but can be freely reformatted or manipulated as required.
  • the technique requires delivery of a gamma-emitting radioisotope into the patient, normally through injection into the bloodstream.
  • a marker radioisotope is attached to a specific ligand to create a radioligand, whose properties bind it to certain types of tissues.
  • This marriage allows the combination of ligand and radiopharmaceutical to be carried and bound to a place of interest in the body, where the ligand concentration is seen by a gamma-camera.
  • the compounds of the present invention comprise a positron emission tomography (PET) label, e.g. a label comprising 18 F, as described elsewhere herein, which allows for the use of said compounds in the non-invasive molecular imaging technique PET.
  • PET is a nuclear medicine, functional imaging technique that produces a three-dimensional image of functional processes in the body.
  • the system detects pairs of gamma rays emitted indirectly by a positron-emitting radionuclide (tracer), which is introduced into the body on a biologically active molecule. Three-dimensional images of tracer concentration within the body are then constructed by computer analysis.
  • the biologically active molecule chosen for PET is generally fluorodeoxyglucose (FDG), an analogue of glucose, the concentrations of tracer imaged will indicate tissue metabolic activity by virtue of the regional glucose uptake.
  • FDG fluorodeoxyglucose
  • many other radioactive tracers can be used in PET to image the tissue concentration of many other types of molecules of interest.
  • the compounds of the present invention comprise optical imaging labels such as dyes, e.g. FITC, DiR or Alexa Fluor® 488 as described elsewhere herein. These dyes are particularly useful in intraoperative applications such as abscess excision, tumor location and size and endoscopy.
  • the compounds of the present invention are covalently linked to fluorophores, e.g. polymethine dyes.
  • optical imaging labels allows for the use of the compounds of the invention in optical imaging techniques.
  • Classical optical imaging techniques rely on the use of visible, ultraviolet, and infrared light in imaging. Chemical imaging or molecular imaging involves inference from the deflection of light emitted from e.g.
  • compounds of the invention comprise an ultrasound label as disclosed elsewhere herein, which allows for the use of the compounds in diagnostic sonography.
  • Ultrasonography is an ultrasound-based diagnostic imaging technique used for visualizing internal body structures including tendons, muscles, joints, vessels and internal organs for possible pathology or lesions.
  • the compounds of the present invention comprise photoacoustic labels (absorbers) as described elsewhere herein.
  • Photoacoustic imaging as a hybrid biomedical imaging modality, is developed based on the photoacoustic effect.
  • photoacoustic labels with and without fluorescence properties can be applied.
  • non-ionizing laser pulses are delivered into biological tissues.
  • radio frequency pulses the technology is referred to as thermoacoustic imaging.
  • the generated ultrasonic waves are then detected by ultrasonic transducers to form images.
  • optical absorption is closely associated with physiological properties.
  • the magnitude of the ultrasonic emission i.e. photoacoustic signal
  • 2D or 3D images of the targeted areas can then be formed.
  • the compounds are preferably employed in the form of a pharmaceutical or diagnostic formulation composition, comprising a pharmaceutically or diagnostically acceptable carrier, diluent or excipient and any of the compound of the present invention.
  • a diagnostic composition comprising any of the compounds of formula (I) comprising a label as described herein above and a pharmaceutically or diagnostically acceptable excipient.
  • the present invention relates to the use of a compound as disclosed herein above for the preparation of a diagnostic composition for diagnosing an inflammatory disease.
  • the term “diagnostic composition” when used herein refers to a composition comprising any one of the compounds of the present invention and a pharmaceutically or diagnostically acceptable carrier, diluent or excipient, which can be applied for used in diagnosis.
  • the carrier used in combination with the compound of the present invention is water-based and forms an aqueous solution.
  • An oil-based carrier solution containing the compound of the present invention is an alternative to the aqueous carrier solution.
  • Either aqueous or oil-based solutions further contain thickening agents to provide the composition with the viscosity of a liniment, cream, ointment, gel, or the like. Suitable thickening agents are well known to those skilled in the art.
  • Alternative embodiments of the present invention can also use a solid carrier containing the diagnostic compound for use in diagnosis as disclosed elsewhere herein. This enables the alternative embodiment to be applied via a stick applicator, patch, or suppository.
  • the solid carrier further contains thickening agents to provide the composition with the consistency of wax or paraffin.
  • compositions include, by the way of illustration and not limitation, diluent, disintegrants, binding agents, adhesives, wetting agents, polymers, lubricants, gliands, substances added to mask or counteract a disagreeable texture, taste or odor, flavors, dyes, fragrances, and substances added to improve appearance of the composition.
  • Acceptable excipients include lactose, sucrose, starch powder, maize starch or derivatives thereof, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, acacia gum, sodium alginate, polyvinyl-pyrrolidone, and/or polyvinyl alcohol, saline, dextrose, mannitol, lactose, lecithin, albumin, sodium glutamate, cysteine hydrochloride, and the like.
  • Suitable excipients for soft gelatin capsules include vegetable oils, waxes, fats, semisolid and liquid polyols.
  • Suitable excipients for the preparation of solutions and syrups include, without limitation, water, polyols, sucrose, invert sugar and glucose.
  • Suitable excipients for injectable solutions include, without limitation, water, alcohols, polyols, glycerol, and vegetable oils.
  • the diagnostic compositions can additionally include preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorings, buffers, coating agents, or antioxidants.
  • Suitable pharmaceutical and diagnostic carriers are described in Remington's Pharmaceutical Sciences, Mack Publishing Company, a standard reference text in this field. The use of the diagnostic composition of the present invention as a diagnostic kit for diagnosing inflammatory disease associated with phagocyte and/or epithelial cell activation and overexpression and accumulation of S100A9 is also encompassed by the present invention.
  • the present invention provides a method of evaluating whether a subject may be at risk of developing an inflammatory disease associated with phagocyte and/or endothelial cell activation in a patient, comprising: (a) administering to said subject any of the compounds as disclosed herein above, (b) detecting the administered compound using an in vivo non-invasive molecular imaging technique, thereby collecting imaging data, and (c) comparing the imaging data received in step b) to reference imaging data.
  • the term “evaluating the risk” refers to any procedure or method used to assess whether or not a subject patient may develop an inflammatory disease associated with phagocyte and/or endothelial cell activation within a specific foreseeable period of time.
  • a method of evaluating the risk of a subject of developing an inflammatory disease might be particularly useful when a subject has already suffered from any of the inflammatory diseases described herein and is of increased risk of recurrence of said disease.
  • the risk of the subject of developing said inflammatory disease can already be detected at an early stage and appropriate therapeutic measures and treatments can be started in time.
  • the S100A9 level in said subject may be determined using any desired technique known to those skilled in the art and methods disclosed herein.
  • a significant increased signal in the imaging data from the subject as compared to reference imaging data indicates that said subject is at higher risk of developing an inflammatory disease associated with phagocyte and/or epithelial cell activation.
  • a signal in the imaging data at a normal level as compared to reference imaging data indicates that said subject is at lower risk of developing an inflammatory disease associated with phagocyte and/or epithelial cell activation.
  • the present invention refers to a method of monitoring or evaluating the progression of an inflammatory disease or disorder associated with phagocyte and/or epithelial cell activation in a patient, the method comprising: (a) administering to said subject any of the compounds as disclosed herein above, (b) detecting the administered compound using an in vivo non-invasive molecular imaging technique, thereby collecting imaging data, and (c) comparing the imaging data received in step (b) to reference imaging data obtained from said patient at an earlier date, wherein the result of the comparison of (c) provides an evaluation of the progression of the inflammatory disease associated with phagocyte and/or epithelial cell activation in said patient.
  • the term “monitoring or evaluating the progression” refers to any procedure or method used in vivo to assess whether or not a patient suffering from an inflammatory disease or disorder associated with phagocyte and/or epithelial cell activation is responsive to treatment with a therapeutic compound.
  • tumor associated inflammation as surrogate marker for e.g. therapy response can also be assessed using any of the methods of the present invention.
  • a method of monitoring or evaluating the progression of an inflammatory disease or disorder relates to monitoring or evaluating the level of S100A9 in a subject at local stage prior, during and after therapy with a therapeutic compound.
  • therapeutic compound refers to any compounds suitable to treat an inflammatory disease characterized by phagocyte and/or epithelial cell activation and overexpression and accumulation of S100A9.
  • a method of monitoring or evaluating the progression of an inflammatory disease or disorder might be particularly useful when treating a patient suffering from an inflammatory disease or disorder associated with phagocyte and/or epithelial cell activation with any medicament for alleviating or healing said inflammatory disease.
  • the method of monitoring as described herein particularly refers to in vivo monitoring the therapeutic efficacy of a drug used in the treatment of inflammatory disorders.
  • conclusions can be drawn during and/or after the treatment of a subject with the medicament as to whether said medicament may improve symptoms of an inflammatory disease when comparing to the physical conditions before start of treatment.
  • such monitoring or evaluation may help an attending physician to obtain the appropriate information to set the appropriate therapy conditions for the treatment of said inflammatory disease.
  • a significantly increased signal in the imaging data from the subject as compared to reference imaging data obtained from said patient at an earlier date indicates a progression of the inflammatory disease associated with phagocyte and/or epithelial cell activation in said patient, whereas no change or decrease in the signal in the imaging data from the subject as compared to reference imaging data obtained from said patient at an earlier date indicates no progression or a regression of the inflammatory disease associated with phagocyte and/or epithelial cell activation in said patient.
  • the present invention provides a method of imaging an inflammatory disease in a subject, comprising: (a) administering to said subject any of the compounds as disclosed herein above, and (b) detecting the administered compound using an in vivo non-invasive molecular imaging method, thereby collecting imaging data.
  • imaging when used herein refers to the optical visualization of low levels of S100A9 or S100A9 accumulation at local site of inflammation under in vivo conditions, using the compounds of the invention comprising a label and any of the molecular imaging techniques described elsewhere herein. Accordingly, the term “imaging” as used herein preferably means “molecular imaging”. Molecular imaging is generally used to explore physiological processes in real-time in vivo and to diagnose or certain diseases due to molecular abnormalities by means of imaging techniques. Moreover, the method of imaging may also be applicable in recurrence diagnosis.
  • the compounds of the present invention are particularly useful to be applied under in vivo conditions, a use of said compounds in vitro is also within the scope of the present invention. Accordingly, the present application provides an in vitro method of diagnosing an inflammatory disease in a subject to whom any of the compound disclosed herein has been pre-delivered, comprising: (a) analyzing a sample taken from said subject, (b) detecting said pre-delivered compound using a non-invasive molecular imaging method, thereby collecting imaging data, (c) comparing the imaging data received in step (b) to reference imaging data.
  • a sample may be analyzed that has been obtained from the subject of the present invention.
  • the sample may be any biological sample taken from said subject and being appropriate to diagnose an inflammatory disease associated with phagocyte and/or epithelial cell activation in said subject.
  • useful samples may include blood samples, tissues samples, body fluid samples, skin samples or any other samples known to those skilled in the art for use in in vitro diagnosis.
  • a compound of formula (I*) or formula (I) may be prepared in a reaction sequence as generally illustrated in Reaction Scheme 1.
  • a primary amide (X*) or (X) is first reacted with an alkyl 3, 3,3-trifluoro-2- oxopropanoate (XI), wherein R 500 is an alkyl group, e.g.
  • a C1-C3 alkyl group such as methyl
  • an organic base e.g. pyridine or triethyl amine
  • a suitable solvent medium e.g. DMF (N,N-dimethylformamide), DMSO (dimethylsulfoxide) or N-methyl pyrrolidine
  • a reagent such as thionyl chloride, thionyl bromide or oxalyl chloride, to provide an "acyl imine intermediate" of the general formula XX* or XX.
  • dichloromethane tetrahydrofuran or a mixture thereof as solvent for this step, preferably dichloromethane.
  • the inventors have surprisingly found that using dichloromethane and/or tetra hydrofuran increases the yield of the compounds of formula (I*) or formula (I). It is also possible to omit the organic base, in particular when dichloromethane, tetrahydrofuran or a mixture thereof is used as solvent.
  • acyl imine (XX*) or (XX) is then reacted with an aminobenzimidazole (XII), optionally in the presence of an organic base, e.g. pyridine or triethyl amine, in a suitable solvent medium, e.g. DMF, DMSO or N-methyl pyrrolidine, to provide the compound of formula (I) or (I*) wherein R A , R B , c, L, and R L are as defined herein. It is also possible to use dichloromethane, tetrahydrofuran or a mixture thereof as solvent for this step, preferably tetrahydrofuran.
  • the inventors have surprisingly found that using dichloromethane and/or tetrahydrofuran increases the yield of the compounds of formula (I*) or formula (I).
  • dichloromethane, tetra hydrofuran or a mixture thereof is used as solvent, it is preferred that the organic base, e.g. pyridine or triethyl amine, more preferably triethyl amine, is present.
  • L* is a linker capable of forming a covalent attachment to a label R L , or L* is a part of a linker capable of forming a covalent attachment to another part of a linker.
  • L* may comprise a functional group which allows covalent attachment of a label or to another part of a linker in a further synthesis step.
  • the functional group may be a leaving group, such as e.g. halogen (F, Cl, Br, I), in particular F, Cl or Br.
  • halogen F, Cl, Br, I
  • Such leaving group can be replaced by a label R L , another part of the linker, or another part of a linker.
  • Reaction Scheme 1 Synthesis of compounds of formula (I*) and (I).
  • R A , R B , Rc, R 500 , L, L* and R L are as defined herein.
  • the present invention also relates to a process for the preparation of a compound of the formula (I*) or its salts, isomers, tautomers or solvates thereof, comprising reacting a compound of the formula (X*) and a compound of the formula (XII) to give a compound of the formula (I*) wherein R 500 is C1-C6 alkyl, preferably methyl or ethyl, more preferably ethyl;
  • L* is a linker capable of forming a covalent attachment to a label R L ; or L* is a part of a linker capable of forming a covalent attachment to another part of a linker;
  • L* may be a linker capable of forming a covalent attachment to a label R L . It is also possible that L* may be a part of a linker capable of forming a covalent attachment to another part of a linker. It is also possible that L* may be a part of a linker capable of forming a covalent attachment to another part of a linker bound to a label. L* may comprise a functional group capable of forming a covalent attachment. As illustrative non-limiting example, the functional group may be a leaving group, such as e.g. halogen (F, Cl, Br, I), in particular F, Cl or Br.
  • the functional group may be a leaving group, such as e.g. halogen (F, Cl, Br, I), in particular F, Cl or Br.
  • L* can be described as L*-FG, wherein FG is a functional group.
  • the functional group FG may be a leaving group.
  • the functional group may be a halogen (F, Cl, Br, I).
  • the functional group may be F, Cl or Br.
  • the functional group may be F or Br.
  • the functional group may be F.
  • the process further comprises reacting the compound of formula (I*) with a label or another part of a linker bound to a label to give a compound of formula (I): wherein R A , R B , Rc, L and R L are as defined herein.
  • the present invention also relates to a process for the preparation of a compound of the formula (I) or its salts, isomers, tautomers or solvates thereof, comprising reacting a compound of the formula (X) with a compound of the formula (XI) and a compound of the formula (XII) to give a compound of the formula (I) wherein R 500 is C1-C6 alkyl, preferably methyl or ethyl, more preferably ethyl; and
  • RA, B, RC, L and R L are as defined herein.
  • the compound of the formula (X) or the compound of the formula (X*) is reacted with the compound of formula (XI) in presence of a solvent.
  • This reaction may be a first step of the reaction sequence.
  • the solvent may be selected from the group consisting of DMF, DMSO, N-methylpyrrolidine, dichloromethane, tetrahydrofuran, and any combination thereof.
  • the solvent is dichloromethane, tetra hydrofuran or a mixture thereof. More preferably, the solvent is dichloromethane.
  • the process further comprises reacting with SOCI 2 , SOBr 2 or oxalyl chloride, preferably SOCI 2 or SOBr 2 , more preferably SOCI 2 . Accordingly, an intermediate which may be formed in the reaction of the compound of the formula (X) or the compound of the formula (X*) with the compound of the formula (XI) may be reacted with SOCI 2 , SOBr 2 or oxalyl chloride.
  • the solvent may be removed (e.g., in vacuo) before adding the SOCI 2 , SOBr 2 or oxalyl chloride.
  • the reacting with the SOCI 2 , SOBr 2 or oxalyl chloride can be carried out without the presence of further solvent, e.g. neat.
  • the process further comprises reacting with the compound of the formula (XII) in presence of a solvent and an organic base to give the compound of the formula (I*) or the compound of the formula (I). Accordingly, an intermediate which may be formed in the reaction with SOCI 2 , SOBr 2 or oxalyl chloride may be reacted with the compound of the formula (XII).
  • the SOCI 2 , SOBr 2 , oxalyl chloride and/or solvent, and or reaction gases are removed (e.g., in vacuo) before adding the compound of formula (XII).
  • the solvent may be selected from the group consisting of DMF, DMSO, N-methylpyrrolidine, dichloromethane, tetrahydrofuran, and any combination thereof.
  • the solvent is dichloromethane, tetrahydrofuran or a mixture thereof. More preferably, the solvent is tetra hydrofuran.
  • the organic base may be triethylamine or pyridine, preferably triethylamine.
  • the process may be carried out as one-pot process.
  • one-pot process in particular means that all steps of forming the compound of formula (I*) or the compound of formula (I) are carried out in one (i.e. the same) reaction vessel. It is possible that during such one-pot process solvent is removed and/or exchanged, and/or that reagents are added. However, in particular, in a one-pot process no work-up (such as, e.g., an aqueous work-up) is carried out between the steps.
  • a work-up may be carried out. Suitable work-up procedures (e.g. aqueous work-up) are known to a person skilled in the art and can be readily selected. If desired, the compound may be further purified. Suitable purification methods (such as, e.g., crystallization or chromatography) are known to a person skilled in the art an can be readily selected.
  • the compound of formula (X*) is , wherein X is F, Cl or Br, preferably F or Br, more preferably F.
  • the compound of formula (X*) is o wherein X is F, Cl or Br, preferably Cl or Br, more preferably Br; and o is an integer ranging from 1 to 15, preferably from 2 to 10, more preferably from 3 to 8, still more preferably from 4 to 6, even more preferably o is 5.
  • the compound of formula (XII) is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-N-phenyl
  • the invention is also characterized by the following items:
  • R A , R B , and R c are each independently selected from H, halogen, cyano, RTO, C1-C6 alkyl optionally substituted by RTO, C3-C6 cycloalkyl optionally substituted by RTO, R 2 C(O), R 3 S, R 4 S(O) 2 , R 5 OC(O), (R 6 ON)C(R 7 ), R 8 R 9 NC(O), R10R11N, RI 2 S(O) 2 NR 13 ,
  • L is a linker
  • R L is a label
  • R B is H and R c is H or halogen; preferably wherein R c is halogen, more preferably Cl.
  • # indicates the attachment point to the label R L .
  • linker L is (L3): (L3), wherein: o is an integer ranging from 1 to 6, preferably from 1 to 4, more preferably from 1 to 3, still more preferably o is 1 or 2, even more preferably o is 1; p is an integer ranging from 1 to 6, preferably from 1 to 4, more preferably from 1 to 3, still more preferably p is 2 or 3, even more preferably p is 2; and
  • # indicates the attachment point to the label R L .
  • R 2 OO is H or C1-C6 alkyl; preferably R 2 oo is C1-C6 alkyl, more preferably C1-C3 alkyl, still more preferably methyl or ethyl, even more preferably methyl;
  • R201 is H or C1-C6 alkyl; preferably R 2 OI is C1-C6 alkyl, more preferably C1-C3 alkyl, still more preferably methyl or ethyl, even more preferably methyl;
  • X is an anion; preferably X is a halogenide, more preferably bromide (Br ); o is an integer ranging from 1 to 15, preferably from 2 to 10, more preferably from 3 to 8, still more preferably from 4 to 6, even more preferably o is 5; p is an integer ranging from 1 to 6, preferably from 1 to 4, more preferably from 1 to 3, still more preferably p is 1 or 2, even more preferably p is 1; q is an integer ranging from 1 to 6, preferably from 1 to 4, more preferably from 1 to 3, still more preferably q is 2 or 3, even more preferably q is 2; and
  • # indicates the attachment point to the label R L .
  • linker L is (L5): wherein R 2O O is H or C1-C6 alkyl; preferably R 200 is C1-C6 alkyl, more preferably C1-C3 alkyl, still more preferably methyl or ethyl, even more preferably methyl; o is an integer ranging from 1 to 15, preferably from 2 to 10, more preferably from 3 to 8, still more preferably from 4 to 6, even more preferably o is 5; and
  • # indicates the attachment point to the label R L .
  • R 2 OO is H or C1-C6 alkyl; preferably R 2 oo is C1-C6 alkyl, more preferably C1-C3 alkyl, still more preferably methyl or ethyl, even more preferably methyl;
  • R 3 OO is H or C1-C6 alkyl; preferably R 300 is C1-C6 alkyl, more preferably C1-C3 alkyl, still more preferably methyl or ethyl, even more preferably methyl;
  • R 30 I is H or C1-C6 alkyl; preferably R 30 I is C1-C6 alkyl, more preferably C1-C3 alkyl, still more preferably methyl or ethyl, even more preferably methyl; o is an integer ranging from 1 to 15, preferably from 2 to 10, more preferably from 3 to 8, still more preferably from 4 to 6, even more preferably o is 5; p is an integer ranging from 1 to 6, preferably from 1 to 4, more preferably from 1 to 3, still more preferably o is 2 or 3, even more preferably p is 2; and
  • # indicates the attachment point to the label R L .
  • R 2O O is H or C1-C6 alkyl; preferably R 200 is C1-C6 alkyl, more preferably C1-C3 alkyl, still more preferably methyl or ethyl, even more preferably methyl;
  • R 20 I is H or C1-C6 alkyl; preferably R 20 I is C1-C6 alkyl, more preferably C1-C3 alkyl, still more preferably methyl or ethyl, even more preferably methyl; o is an integer ranging from 1 to 15, preferably from 2 to 10, more preferably from 3 to 8, still more preferably from 4 to 6, even more preferably o is 5; and
  • # indicates the attachment point to the label R L .
  • R 2 OO is H or C1-C6 alkyl; preferably R 200 is C1-C6 alkyl, more preferably C1-C3 alkyl, still more preferably methyl or ethyl, even more preferably methyl;
  • R 20 I is H or C1-C6 alkyl; preferably R 20 I is C1-C6 alkyl, more preferably C1-C3 alkyl, still more preferably methyl or ethyl, even more preferably methyl; R 3O O is H or C1-C6 alkyl; preferably R 300 is C1-C6 alkyl, more preferably C1-C3 alkyl, still more preferably methyl or ethyl, even more preferably methyl;
  • R301 is H or C1-C6 alkyl; preferably R 30 I is C1-C6 alkyl, more preferably C1-C3 alkyl, still more preferably methyl or ethyl, even more preferably methyl; o is an integer ranging from 1 to 15, preferably from 2 to 10, more preferably from 3 to 8, still more preferably from 4 to 6, even more preferably o is 5; p is an integer ranging from 1 to 6, preferably from 1 to 4, more preferably from 1 to 3, still more preferably o is 2 or 3, even more preferably p is 2; and
  • o is an integer ranging from 1 to 6, preferably from 1 to 4, more preferably from 1 to 3, still more preferably o is 1 or 2, even more preferably o is 1;
  • p is an integer ranging from 1 to 10, preferably from 1 to 8, more preferably from 2 to 5, still more preferably p is 3 or 4, even more preferably p is 3;
  • q is an integer ranging from 1 to 5, preferably from 1 to 3;
  • # indicates the attachment point to the label R L .
  • # indicates the attachment point to the label R L .
  • linker L is (L11): wherein o is an integer ranging from 1 to 6, preferably from 1 to 4, more preferably from 1 to 3, still more preferably o is 1 or 2, even more preferably o is 1; p is an integer ranging from 1 to 10, preferably from 2 to 8, more preferably from 2 to 6, still more preferably p is 2 or 4, even more preferably p is 3; and
  • # indicates the attachment point to the label R L .
  • linker L is (L12): (L12), wherein o is an integer ranging from 1 to 20, preferably from 2 to 15, more preferably from 3 to 10, still more preferably from 4 to 6, even more preferably o is 5; R 2 OO is H or C1-C6 alkyl; preferably R 2 oo is H; and
  • # indicates the attachment point to the label R L .
  • the label R L is any one of a single photon emission tomography (SPECT) label, a positron emission tomography (PET) label, an optical imaging label, a magnetic resonance imaging (MRI) label, an ultrasound label or a photoacoustic imaging label.
  • SPECT single photon emission tomography
  • PET positron emission tomography
  • MRI magnetic resonance imaging
  • ultrasound label ultrasound label or a photoacoustic imaging label.
  • linker L is selected from the group consisting of (L1), (L3), (L3*), (L4), (L4*), (L5), (L5*), (L6), (L6*), (L7), (L7*), (L8) and (L8*), wherein (L1), (L3), (L3*), (L4), (L4*), (L5), (L5*), (L6), (L6*), (L7), (L7*), (L8) and (L8*), wherein (L1), (L3), (L3*), (L4), (L4*), (L5), (L5*), (L6), (L6*), (L7), (L7*), (L8) and (L8*) are as defined in any one of the preceding claims.
  • the compound is selected from the group consisting of
  • the dye is selected from the group consisting of fluorescein isothiocyanate (FITC), 1 ,1'-dioctadecyl-3,3,3',3'-tetramethyl indotricarbocyanine iodide (DiR), a coumarin dye, a rhodamine dye, a carbopyronin dye, an oxazine dye, a fluorescein dye, a cyanine dye, a boron-dipyrromethene (BODIPY) dye, a squaraine dye, and a squaraine rotaxane dye.
  • FITC fluorescein isothiocyanate
  • DIR 1 ,1'-dioctadecyl-3,3,3',3'-tetramethyl indotricarbocyanine iodide
  • LiR fluorescein isothiocyanate
  • LiR 1 ,1'-
  • a diagnostic composition comprising a compound according to any one of claims 1 to 80 and a pharmaceutically or diagnostically acceptable excipient.
  • inflammatory disease comprises dermatitis, atherosclerosis, psoriasis, autoimmune diseases, arthritis, allergies, cardiovascular processes, local and systemic infections, neuroinflammatory diseases, acute lung injury (ALI) and tumors.
  • the compound for use according to item 87, wherein the method is any one of single photon emission tomography (SPECT), positron emission tomography (PET), optical imaging, magnetic resonance imaging (MRI), ultrasound or photoacoustic imaging.
  • SPECT single photon emission tomography
  • PET positron emission tomography
  • MRI magnetic resonance imaging
  • ultrasound photoacoustic imaging
  • a method of diagnosing an inflammatory disease in a subject comprising: a) administering to said subject a compound according to any one of items 1 to 80, b) detecting the administered compound using an in vivo non-invasive molecular imaging technique, thereby collecting imaging data, c) comparing the imaging data received in step b) to reference imaging data.
  • a non-invasive method of detecting or imaging accumulation of S100A9 in the body of a subject to whom a compound of any one of items 1 to 80 has been pre-delivered comprising: a) detecting the administered compound using an in vivo non-invasive molecular imaging technique, thereby collecting imaging data, b) comparing the imaging data received in step a) to reference imaging data.
  • the inflammatory disease comprises dermatitis, atherosclerosis, psoriasis, autoimmune diseases, arthritis, allergies, cardiovascular processes, local and systemic infections, neuroinflammatory diseases, acute lung injury (ALI) and tumors.
  • a method for evaluating whether a subject may be at risk of developing an inflammatory disease associated with phagocyte and/or epithelial cell activation comprising: a) administering to said subject a compound according to any one of items 1 to 80, b) detecting the administered compound using an in vivo non-invasive molecular imaging technique, thereby collecting imaging data, c) comparing the imaging data received in step b) to reference imaging data.
  • a significantly increased signal in the imaging data from the subject as compared to reference imaging data indicates that said subject is at higher risk of developing an inflammatory disease associated with phagocyte and/or epithelial cell activation.
  • a method of monitoring or evaluating the progression of an inflammatory disease associated with phagocyte and/or epithelial cell activation in a patient comprising: a) administering to said subject a compound according to any one of items 1 to 80, b) detecting the administered compound using an in vivo non-invasive molecular imaging technique, thereby collecting imaging data, c) comparing the imaging data received in step b) to reference imaging data obtained from said patient at an earlier date, wherein the result of the comparison of c) provides an evaluation of the progression of the inflammatory disease associated with phagocyte and/or epithelial cell activation in said patient.
  • a method of imaging an inflammatory disease in a subject comprising: a) administering to said subject a compound according to any one of items 1 to 80, b) detecting the administered compound using an in vivo non-invasive molecular imaging method, thereby collecting imaging data.
  • An in vitro method of diagnosing an inflammatory disease in a subject to whom a compound according to any one of items 1 to 80 has been pre-delivered comprising: a) analyzing a sample taken from said subject, b) detecting said pre-delivered compound using a non-invasive molecular imaging method, thereby collecting imaging data, c) comparing the imaging data received in step b) to reference imaging data.
  • a process for the preparation of a compound of the formula (I*) or its salts, isomers, tautomers or solvates thereof, comprising reacting a compound of the formula (X*) and a compound of the formula (XII) to give a compound of the formula (I*) wherein R 500 is C1-C6 alkyl, preferably methyl or ethyl, more preferably ethyl;
  • L* is a linker capable of forming a covalent attachment to a label R L ;
  • L* is a part of a linker capable of forming a covalent attachment to another part of a linker
  • R A , R B and R c are as defined in any one of items 1 to 80.
  • RA, B, RC, L and R L are as defined in any one of items 1 to 80.
  • Example 1 Development of new diagnostic imaging tracers based on benzimidazoles
  • Characteristic for the lead structure is a flat tricyclic system with a sp 3 - hybridized carbon atom bearing an amide group and a trifluoromethyl group.
  • [ 19 F]SST034 was the first target molecule, using 6- fluoro-2-pyridine-carboxamide (1), ethyl 3,3,3-trifluoropyruvate (2) and dichloro benzimidazole derivative 4 for the preparation (Scheme 1).
  • [ 19 F]SST034 is not only an intermediate in the synthesis of further functionalized structures, but with its 19 F-substituted pyridine it may also act as a non-radioactive reference compound.
  • Scheme 1 Reaction sequence to build up the benzimidazole lead structure.
  • Scheme 3 Synthesis of precursors, first radio tracers and optical compounds.
  • Example 2a In vitro binding assay
  • Figure 8 shows three separate runs for determining the equilibrium binding constant K d of fluorescein-labelled derivative 6-FAM-SST177 towards mS100A9 in accordance with Example 2. Depicted is the fluorescence intensity (Fl, vertical axis) depending of the concentration of mS100A9 in pM (horizontal axis).
  • Example 2b K D determination of AF488-SST193 against murine and human S100A9
  • mS100A9 was diluted from a 111 pM stock solution in HPS (pH 7.4), stored at -20 °C in aliquots.
  • the protein stock solutions were diluted with ice-cooled assay buffer (Tris (50 mM Tris, 100 mM NaCI, 1 mM CaCI 2 , pH 7.4) or HPS (50 mM HEPES, 1 mM CaCI 2 , pH 7.4)) and treated with ZnCI 2 (5 x 0.4 eq., gentle mixing in between additions).
  • AF488-SST193 was diluted from a 1 mM DMSO stock solution and stored at -20 °C under exclusion of light.
  • Bmax total number of binding sites
  • K o equilibrium dissociation constant
  • c pro t e in protein concentration
  • mP milli-polarization
  • / ⁇ fluorescence intensity perpendicular to linear polarized excitation light
  • o* standard error of the mean
  • a standard deviation.
  • Table 1 shows the determined K D of AF488-SST193 towards S100-Proteins given as average over n individual experiments with standard error of the mean (o- x ). Calculations were done according to equations 05 and in a “one-site - specific binding” fitting model.
  • Figure 9 shows saturation binding curves (“one-site - specific binding” model) determining the K D of AF488-SST193 towards A) mS100A9 in HPS buffer, B) mS100A9 in Tris buffer, C) hS100A9C3S in Tris buffer and D) mS100A8 in HPS buffer as a negative control.
  • Each curve refers to an individual experiment with date given in the legend.
  • Example 3 In vivo imaging (Cy5.5-SST110) - ear inflammation model of irritant contact dermatitis
  • Balb/c mice Harlan Laboratories
  • S100A9-deficient mice S100A9' /_
  • backcrossed from C57BL/6 to Balb/c background F10 generation
  • mice backcrossed from C57BL/6 to Balb/c background (F10 generation) were used at the age of 10- to 14 weeks, sex and age matched for each set of experiments and housed under specific pathogen-free conditions.
  • the dermatitis mouse model showed significant accumulation of Cy5.5-SST 110 (i.e. a compound of formula (I) in accordance with the present invention, which is covalently linked to a label) at sites of inflammation.
  • Cy5.5- SST110 showed significant accumulation in the inflamed ear of a dermatitis mouse model. This can be explained by binding of the compound Cy5.5-SST110 to S100A9 accumulated in the inflamed ear tissue. On the other hand, no significant accumulation of Cy5.5-SST110 was observed in in the control ear without inflammation.
  • Figure 1 shows in vivo imaging using the compound Cy5.5-SST110 in an ear inflammation mouse model of irritant contact dermatitis.
  • First PET radio tracer [ 18 F]SST034 was obtained using a nucleophilic aromatic substitution reaction of bromo-precursor SST074 at 160 °C for 20 min with K 18 F and azacryptant K 2 22- The compound was found to be stable in murine and human blood serum over a period of at least 120 min and the experimental logD- value was determined as 1.7 +/- 0.2.
  • Figure 2 shows the murine and human blood serum stability of the compound [ 18 F]SST034 over 120 min.
  • Second radio tracer [ 18 F]SST096 was obtained by [3+2] dipolar cycloaddition with [ 18 F]fluoroethyl azide as a prostetic group. This tracer was again stable in murine and human blood serum for over 120 min. The experimental logD value of 1.3 +/- 0.2 was observed to be more hydrophilic than [ 18 F]SST034.
  • Cationic radio tracer [ 18 F]SST120 was obtained by the same strategy as [ 18 F]SST096 “click-chemistry” and [ 18 F]fluoroethyl azide as a prostetic group.
  • the cationic tracer was stable in murine and human blood serum for 120 min and the experimental logD value was 0.1 +/- 0.09. This shows an increase of hydrophilicity compared to the previous tracers, but still its better soluble in organic solvents than in water, as the positive logD value states.
  • Figure 4 shows the murine and human blood serum stability of the compound [ 18 F]SST120 over 120 min.
  • Figure 5 shows in vivo biodistribution studies with the compound [ 18 F]SST034.
  • Figure 5A shows maximum intensity projections of selected time frames in vivo).
  • Figure 5B shows an ex vivo gamma counter analysis (110 min p.i.).
  • In vivo imaging depicts fast kinetics of [ 18 F]SST034 after i.v. injection with predominant hepatobiliary clearance. Accumulation of radioactivity in the bones as surrogate marker for defluorination of [ 18 F]SST034 was not observed. Furthermore, already 30 minutes after tracer injection tissues that are not involved in tracer elimination present only with low levels of radioactivity. The low background activities are favourable for diagnostic application of [ 18 F]SST034 in vivo as they allow sensitive detection of pathological tracer accumulation with a good contrast.
  • Figure 6 shows In vivo biodistribution studies with the compound [ 18 F]SST120.
  • Figure 6A shows Maximum Intensity Projections of selected time frames ⁇ in vivo).
  • Figure 6B shows an ex vivo gamma counter analysis (110 min p.i.).
  • [00294] In vivo imaging depicts fast kinetics of [ 18 F]SST096 after i.v. injection with predominant hepatobiliary clearance.
  • the elimination pathway has slightly shifted towards renal excretion as depicted by accumulation of radioactivity in the urinary bladder and confirmed by ex vivo gamma counter analysis. Accumulation of radioactivity in the bones as surrogate marker for defluorination of [ 18 F]SST096 was not observed.
  • already 60 minutes after tracer injection tissues that are not involved in tracer elimination present only with low levels of radioactivity.
  • the low background activities are favourable for diagnostic application of [ 18 F]SST096 in vivo as they allow sensitive detection of pathological tracer accumulation with a good contrast.
  • Figure 7 shows in vivo biodistribution studies with the compound [ 18 F]SST120.
  • Figure 7A shows Maximum Intensity Projections of selected time frames in vivo).
  • Figure 7B shows an ex vivo gamma counter analysis (110 min p.i.).
  • [00296] In vivo imaging depicts fast kinetics of [ 18 F]SST120 after i.v. injection with again predominant hepatobiliary clearance. However, in comparison to [ 18 F]SST096 the elimination pathway has again slightly shifted towards renal excretion, resulting in high radioactivity concentrations in the urine as measured by gamma counting 110 min p.i..
  • Radiosynthesis was performed using Milli-Q® (Merck) purified water and dried solvents of highest purity, as well as solvents for clinical radiochemistry in septum bottles by ABX.
  • analytic and semi-preparative (radio-)HPLC separations the following reverse phase systems of Knauer with UV and y-ray detectors were utilized: analytic RP- HPLC with two Smartline 1000 pumps (Knauer), Smartline 2500 UV detector (Knauer), GabiStar y-ray detector of Raytest Isotopenmessgerate. Radio-semipreparative RP-HPLC with Knauer's K-500, K-501 pumps and K-2000 UV detector, Nal(TI) Scintibloc 51 SP51 y- ray detector of Crismatec.
  • Non-radioactive semipreparative purification was performed on a Knauer Azura 2.1L system with two Azura pump P2.1L, two Azura assistant ASM 2.1 L, Azura control unit CU 2.1 L and a Azura UVD 2.1 L UV-detector.
  • Mass spectra were measured at the mass spectrometry department in the Organisch-Chemisches Institut of the Westfalische Wilhelms-Universitat Munster, using electrospray ionization (ESI) technique on the following instruments: MicroToF of Bruker Daltonics, Orbitrap LTQ XL of Thermo Scientific. The exact masses of new compounds were determined with manual loop injection and electrospray ionization on these instruments, as well. Previously to each exact mass measurement the instrument was calibrated with sodium formiate clusters.
  • EI electrospray ionization
  • Fluorescence polarization assay was performed on a Flexstation 3 multimodal plate reader by MolecularDevices (San Jose, USA).
  • [ 18 F]fluoride was eluted in the reactor with a solution of azacryptant K 222 (20 mg, 53 pmol) in potassium carbonate solution (1 m, 40 pl), acetonitrile (800 pL) and Milli-Q® water (200 pL) or a premixed solution by ABX was used Additionally, the anion exchange cartridge was flushed with acetonitrile (200 pl). For azeotropic drying the reactor was evacuated and solvents were evaporated at 56 °C with (2 min) and without He- stream (1 min) applied. For further drying, the reactor was heated to 84 °C under vacuum for 10 min. Dried no carried added [ 18 F]fluoride was used in the individual labeling reactions.
  • Radiochemical yields refer to the fraction of the final radiotracer reconstituted in a physiological solution (200 pL, PBS buffer, saline, buffer/EtOH 10 %, etc) over starting activity of the applied no carrier added [ 18 F]fluoride RCY is given including decay corrections (d.c.).
  • Radiochemical purity was determined by analytical radio-HPLC and refers to the percentage of activity of the radiotracer in the semi preparative HPLC purified solution.
  • the partition coefficient was determined in a higher dilution by “washing” the n-octanol phase with PBS buffer. After vigorous shaking for 1 min, a mixture of the radiotracer (20-30 kBq) in PBS buffer (500 pL) and n-octanol (500 pL) was centrifuged (2 min, 3000 rpm). A fraction (400 pL) of the n-octanol layer was removed and mixed vigorously with PBS buffer (400 pL).
  • the layers were separated by centrifugation (2 min, 3000 rpm) and three aliquots (100 pL) of both phases were measured with gamma counter Wallac Wizard 3 (PerkinElmer Life Sciences) in the form of decay corrected double determinations.
  • the radioactivity in each layer was calculated as a mean value of corresponding aliquots.
  • the logD exp value was calculated as the logarithmic quotient of the measured radioactivity in both layers:
  • Blood serum samples were obtained by centrifugation (5000 rpm, 10 min, centrifuge) of a blood sample and removing the serum as centrifugate.
  • Blood serum for stability test was either freshly prepared before testing or stored at -18 °C.
  • Fluorescence reflectance imaging was performed 3h after tracer application (i.v. injection into the tail vein), corresponding to 27 h after croton oil treatment.
  • In vivo fluorescence reflectance imaging was performed with an I VIS Spectrum small-animal imaging system (Perkin Elmer). Images were acquired and analyzed using Living Image 4.X software (Perkin Elmer). For the measurements the Cy5.5® filter set was used. Identical excitation/emission settings were used for all experiments. Fluorescence emission was measured by Fluorescence emission radiance per incident excitation irradiance (p/sec/cm2/sr / pW/cm2).
  • PET imaging studies were carried out using a submillimeter high resolution (0.7 mm full width at half-maximum) small animal scanner (32 module quadHIDAC, Oxford Positron Systems Ltd., Oxford, UK) with uniform spatial resolution ( ⁇ 1 mm) over a large cylindrical field (165 mm diameter, 280 mm axial length).
  • List-mode data were acquired for 90 min and reconstructed into dynamic time frames using an iterative reconstruction algorithm.
  • the scanning bed was transferred to the computed tomography (CT) scanner (Inveon, Siemens Medical Solutions, U.S.), and a CT acquisition with a spatial resolution of 80 pm was performed for each mouse.
  • CT computed tomography
  • Reconstructed image data sets were coregistered based on extrinsic markers attached to the multimodal scanning bed and the inhouse developed image analysis software MEDgical.
  • Three-dimensional volumes of interest (VOIs) were defined over the respective organs in CT data sets, transferred to the coregistered PET data, and analyzed quantitatively.
  • Regional uptake was calculated as percentage of injected dose by dividing counts per milliliter in the VOI by total counts in the mouse multiplied by 100 (%ID/mL).
  • mice were euthanized by cervical dislocation and a necropsy was performed. Ex vivo biodistribution of radioactivity was analyzed by scintillation counting (Wizard2 gamma counter, Perkin-Elmer Life Science) and the radioactivity in respective organs decay-corrected and calculated as %ID per gram tissue (% I D/g).
  • Radiochemical purity was determined by analytical radio-HPLC (column: RP Eurosphere-2, 100-5, C18, 150 x 4 mm), mobile phase: Milli-Q® water (0.1 % TFA)/acetonitrile (0.1 % TFA) , flow: 1.0 mL/min, gradient see below). Solvents were evaporated under reduced pressure at 70 - 80 °C until a vacuum of ca. 5 mbar was reached. The radiotracer was dissolved in EtOH (20 pL), diluted with PBS buffer (180pL) and transferred to an eppendorf tube for further experiments.
  • Semi preparative radio-HPLC gradient isocratic 90 % water (0.1 % TFA) for 1 min, gradient to 55 % water (0.1 % TFA) within 1 min, gradient to 20 % water (0.1 % TFA) within 11 min, gradient to 90 % water (0.1 % TFA) within 1 min.
  • Analytical radio-HPLC gradient isocratic 90 % water (0.1 % TFA) for 1 min, gradient to 55 % water (0.1 % TFA) within 1 min, gradient to 20 % water (0.1 % TFA) within 11 min, gradient to 90 % water (0.1 % TFA) within 1 min.
  • the product fraction was collected in previously silanized glassware (Sigmacote®, sigma-aldrich). Radiochemical purity was determined by analytical radio-HPLC (column: RP Eurosphere-2, 100-5, C18, 150 x 4 mm), mobile phase: Milli-Q® water (0.1 % TFA)/acetonitrile (0.1 % TFA) , flow: 1.0 mL/min, gradient see below). Solvents were evaporated under reduced pressure at 70 - 80 °C until a vacuum of ca. 5 mbar was reached. The radiotracer was dissolved in EtOH (20 pL), diluted with PBS buffer (180pL) and transferred to an eppendorf tube for further (biological) experiments. [00322] The experimental n-octanol/PBS buffer partition coefficient (logD exp ), as well as the blood serum stability of [ 18 F]SST034 were determined applying general procedures, respectively.
  • Analytical radio-HPLC gradient isocratic 80 % water (0.1 % TFA) for 2 min, gradient to 55 % water (0.1 % TFA) within 1 min, gradient to 30 % water (0.1 % TFA) within 9 min, gradient to 80 % water (0.1 % TFA) within 2 min.
  • the product fraction was collected in previously silanized glassware (Sigmacote®, sigma-aldrich). Radiochemical purity was determined by analytical radio-HPLC (column: RP Eurosphere-2, 100-5, C18, 150 x 4 mm), mobile phase: Milli-Q® water (0.1 % TFA)/acetonitrile (0.1 % TFA) , flow: 1.0 mL/min, gradient see below). Solvents were evaporated under reduced pressure at 70 - 80 °C until a vacuum of ca. 5 mbar was reached. The radiotracer was dissolved in EtOH (20 pL), diluted with PBS buffer (180pL) and transferred to an eppendorf tube for further (biological) experiments.
  • Analytical radio-HPLC gradient isocratic 90 % water (0.1 % TFA) for 2 min, gradient to 65 % water (0.1 % TFA) within 1 min, gradient to 50 % water (0.1 % TFA) within
  • 6-fluoropicolinamide (3.50 g, 25.0 mmol, 1.0 eq.) was suspended in dry DCM (15 mL).
  • Ethyl-3,3,3-trifluoro-2- oxopropanoate (5.00 g, 29.4 mmol, 1.2 eq.) was added dropwise and the reaction mixture was stirred at room temperature for 2h until the substrates were completely dissolved.
  • Solvent was removed in vacuo and the reaction mixture was dissolved in SOCI 2 (15 mL). The reaction mixture was stirred at 60 °C for 15 h.
  • Benzimidazole SST034 400 mg, 0.89 mmol, 1 eq. was dissolved in a mixture of propargylamine/pyridine (1 :1, 0.5 mL) and stirred in a sealed tube at 100 °C for 48 h. After cooling to room temperature and releasing pressure the reaction mixture was concentrated in vacuo. The brownish residue was suspended in 0.1 m HCI (2 mL) and the aqueous phase was extracted three times with EE. The combined organic layers were dried over MgSO 4 and the solvent was removed under reduced pressure.
  • the product was purified via flash column chromatography (DCM/MeOH 2.5-5% and additional 1% TEA), followed by washing the product fraction with 0.1 m HCI until the aqueous layer was acidic. The organic layer was dried over MgSO 4 and concentrated under reduced pressure, yielding alkyne SST093 as a white solid.
  • a catalyst solution was prepared by vigorously mixing CuSO 4 5 H 2 O (16 mg, 0.1 mmol, 0.5 eq.) and sodium ascorbate (44 mg, 0.22 mmol, 1.1 eq.) in water (1 ml) for 5 min until the solution turned cloudy orange. After addition of the catalyst solution to the reaction mixture, it was stirred at room temperature for 2h. The reaction mixture was diluted with ethyl acetate (50 ml) and washed with NH 3 -solution (10%, neutralized with NH 4 CI to pH 7-8, 50 ml). The aqueous phase was extracted with ethyl acetate (2x50 ml). The combined organic layers were washed with sat.
  • the reaction mixture was directly purified via semipreparative RP- HPLC in 5-8 separate runs (column: Knauer Eurosphere 100-5 C18 250 x 8 mm, mobile phase: Milli-Q® water (0.1 % TFA)/acetonitrile (0.1 % TFA) , flow: 5.5 mL/min, gradient see below)).
  • the combined product fractions were lyophilized, after removing organic solvent via roto-evaporation.
  • the product was obtained as a dark-blue solid (0.37 mg, 0.23 pmol, 11 %).
  • the compound was stored in an aqueous stock solution at -30°C protected from light. Structure and purity of the compound were confirmed by HR-ESI(-)-MS and RP-HPLC.
  • the product was obtained by silica column filtration (DCM/MeOH 9:1 to MeOH) and reverse phase column chromatograph (H 2 O/MeOH 40 % to 70 % over 10 column volumes) as a white solid (210 mg, 0.36 mmol, 36 %).
  • a catalyst solution was prepared by vigorously mixing CuSO 4 5 H 2 O (42 mg, 0.17 mmol, 0.5 eq.) and sodium ascorbate (67 mg, 0.34 mmol, 1.0 eq.) in water (2 ml) for 5 min until the solution turned cloudy orange. After addition of the catalyst solution to the reaction mixture, it was stirred at room temperature for 16h. The solvent was removed under reduced pressure. The crude product was obtained by filtration over a short silica plug (DCM -> DCM/MeOH 1 :1 -> MeOH). Applying automated reverse phase column chromatography (H 2 O/MeOH 40 % to 70 % over 10 column volumes) and lyophilization, tracer reference compound SST120 was obtained as a white solid (70 mg, 0.1 mmol, 30%).
  • the reaction mixture was directly purified via semipreparative RP-HPLC in 10-12 separate runs (column: Knauer Eurosphere 100-5 C18 250 x 8 mm, mobile phase: Milli-Q® water / acetonitrile, flow: 5.5 mL/min, gradient see below).
  • the combined product fractions were lyophilized, after removing organic solvent via roto-evaporation.
  • the product was obtained as a reddish/pink solid (1.14 mg, 1.15 pmol, 15 %).
  • the compound was stored in an DMSO stock solution at -30°C protected from light. Structure and purity of the compound were confirmed by HR-ESI(-)-MS and RP- HPLC.
  • the reaction mixture was directly purified via semipreparative RP-HPLC in 10-12 separate runs (column: Knauer Eurosphere 100-5 C18 250 x 8 mm, mobile phase: Milli-Q® water / acetonitrile, flow: 5.5 mL/min, gradient see below).
  • the combined product fractions were lyophilized, after removing organic solvent via roto-evaporation.
  • the product was obtained as a reddish/pink solid (1.25 mg, 1.30 pmol, 17 %).
  • the compound was stored in an DMSO stock solution at -30°C protected from light. Structure and purity of the compound were confirmed by HR-ESI(-)-MS and RP- HPLC.
  • the reaction mixture was directly purified via semipreparative RP-HPLC in 5-8 separate runs (column: Knauer Eurosphere 100-5 C18 250 x 8 mm, mobile phase: MilliCi® water / acetonitrile, flow: 5.5 mL/min, gradient see below).
  • the combined product fractions were lyophilized, after removing organic solvent via roto-evaporation.
  • the product was obtained as a light green solid (1.97 mg, 2.09 pmol, 33.6 %).
  • the compound was stored in an DMSO stock solution or solid at -30°C protected from light. Structure and purity of the compound were confirmed by HR-ESI(-)-MS and RP-HPLC.
  • the combined product fractions were lyophilized, after removing organic solvent under reduced pressure, which yielded SST191 as a white powder (6 mg, 12.6 pmol, 12 %).
  • NMR revealed that after HPLC purification with 0.1 % TFA in the eluent at least partially chloride was exchanged for TFA as counter-anion.
  • AF488-SST193 Bis(triethylammonium) 2-(6-amino-3-iminio-4,5-disulfonato-3H- xanthen-9-yl)-5-((6-((6,7-dichloro-2-oxo-3-(trifluoromethyl)-2,3-dihydro-1H- benzo[c/]imidazo[1,2-a]imidazol-3-yl)amino)-6-oxohexyl)carbamoyl)benzoate
  • the reaction mixture was shaken in a black reaction tube for 16 h and directly purified by means of semipreparative RP-HPLC in 5-8 separate runs (column: Knauer Eurosphere 100-5 C18 250 x 8 mm, mobile phase: Milli-Q® H 2 O / ACN, flow: 5.5 mL/min, gradient see below).
  • the product fractions were combined and the organic solvent was evaporated under reduced pressure. Subsequently, the product was obtained by lyophilization as a light green solid (0.51 mg, 0.441 pmol, 32 %).
  • the compound was stored in a DMSO stock solution or solid at -30°C protected from light.
  • the structure of the compound was confirmed by HR-ESI(-)-MS and purity was determined as 97.5 % using semipreparative RP-HPLC with the separation gradient (Chromatogram is given at the end of this subchapter 4.5.2).

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Abstract

La présente invention concerne un composé de formule (I), ou un sel, un isomère ou un tautomère de celui-ci ; RA, RB et RC étant tels que définis dans la description ; L étant un lieur ; et RL étant une étiquette. De tels composés peuvent être utilisés dans le diagnostic d'une maladie inflammatoire au niveau d'un site local.
PCT/EP2023/061215 2022-04-29 2023-04-28 Benzo[d]imidazo[1,2-a]imidazoles et leur utilisation dans le diagnostic WO2023209141A1 (fr)

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WO2015177367A1 (fr) 2014-05-23 2015-11-26 Active Biotech Ab Nouveaux composés utiles en tant qu'inhibiteurs de s100
WO2016067238A1 (fr) 2014-10-29 2016-05-06 Westfaelische Wilhelms-Universitaet Muenster Composés de quinoline-3-carboxamide et leur utilisation en diagnostic

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