WO2019180475A1 - Colorants d'azacyanine et leur utilisation - Google Patents
Colorants d'azacyanine et leur utilisation Download PDFInfo
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- WO2019180475A1 WO2019180475A1 PCT/IB2018/000390 IB2018000390W WO2019180475A1 WO 2019180475 A1 WO2019180475 A1 WO 2019180475A1 IB 2018000390 W IB2018000390 W IB 2018000390W WO 2019180475 A1 WO2019180475 A1 WO 2019180475A1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09B—ORGANIC DYES OR CLOSELY-RELATED COMPOUNDS FOR PRODUCING DYES, e.g. PIGMENTS; MORDANTS; LAKES
- C09B23/00—Methine or polymethine dyes, e.g. cyanine dyes
- C09B23/0075—Methine or polymethine dyes, e.g. cyanine dyes the polymethine chain being part of an heterocyclic ring
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- A61K49/0013—Luminescence
- A61K49/0017—Fluorescence in vivo
- A61K49/0019—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules
- A61K49/0021—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules the fluorescent group being a small organic molecule
- A61K49/0032—Methine dyes, e.g. cyanine dyes
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- A61K49/0052—Small organic molecules
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- A61K49/0013—Luminescence
- A61K49/0017—Fluorescence in vivo
- A61K49/005—Fluorescence in vivo characterised by the carrier molecule carrying the fluorescent agent
- A61K49/0056—Peptides, proteins, polyamino acids
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- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0013—Luminescence
- A61K49/0017—Fluorescence in vivo
- A61K49/005—Fluorescence in vivo characterised by the carrier molecule carrying the fluorescent agent
- A61K49/0058—Antibodies
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/006—Biological staining of tissues in vivo, e.g. methylene blue or toluidine blue O administered in the buccal area to detect epithelial cancer cells, dyes used for delineating tissues during surgery
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/04—Organic compounds
- A61K51/0497—Organic compounds conjugates with a carrier being an organic compounds
-
- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09B—ORGANIC DYES OR CLOSELY-RELATED COMPOUNDS FOR PRODUCING DYES, e.g. PIGMENTS; MORDANTS; LAKES
- C09B23/00—Methine or polymethine dyes, e.g. cyanine dyes
- C09B23/0008—Methine or polymethine dyes, e.g. cyanine dyes substituted on the polymethine chain
- C09B23/0016—Methine or polymethine dyes, e.g. cyanine dyes substituted on the polymethine chain the substituent being a halogen atom
-
- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09B—ORGANIC DYES OR CLOSELY-RELATED COMPOUNDS FOR PRODUCING DYES, e.g. PIGMENTS; MORDANTS; LAKES
- C09B23/00—Methine or polymethine dyes, e.g. cyanine dyes
- C09B23/0008—Methine or polymethine dyes, e.g. cyanine dyes substituted on the polymethine chain
- C09B23/0025—Methine or polymethine dyes, e.g. cyanine dyes substituted on the polymethine chain the substituent being bound through an oxygen atom
-
- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09B—ORGANIC DYES OR CLOSELY-RELATED COMPOUNDS FOR PRODUCING DYES, e.g. PIGMENTS; MORDANTS; LAKES
- C09B23/00—Methine or polymethine dyes, e.g. cyanine dyes
- C09B23/0008—Methine or polymethine dyes, e.g. cyanine dyes substituted on the polymethine chain
- C09B23/0033—Methine or polymethine dyes, e.g. cyanine dyes substituted on the polymethine chain the substituent being bound through a sulfur atom
-
- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09B—ORGANIC DYES OR CLOSELY-RELATED COMPOUNDS FOR PRODUCING DYES, e.g. PIGMENTS; MORDANTS; LAKES
- C09B23/00—Methine or polymethine dyes, e.g. cyanine dyes
- C09B23/0008—Methine or polymethine dyes, e.g. cyanine dyes substituted on the polymethine chain
- C09B23/0041—Methine or polymethine dyes, e.g. cyanine dyes substituted on the polymethine chain the substituent being bound through a nitrogen atom
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/58—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving labelled substances
- G01N33/582—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving labelled substances with fluorescent label
Definitions
- fluorescent dyes which are cyanine dyes that incorporate additional aza moieties in the indolenium heterocycles and/or in the methine chains connecting them.
- Symmetrical and unsymmetrical chemically reactive azacyanine dyes are described for conjugation, as well as their bioconjugates for in-vitro and in-vivo assays and fluorescence imaging.
- Fluorescent dyes form the building blocks of many reagents that are used in a myriad of bioanalytical applications such as nucleic acid detection and sequencing, flow cytometry for cellular characterization, fluorescence microscopy, enzymatic assays and increasingly in the field of optical imaging as probes to detect disease tissue and organ in vivo.
- fluorescent dyes available for use in microscopy, immunohistology, and other high technology research. These dyes have extended conjugated carbon chains embedded in their chemical structures. The molecules are able to absorb light energy and emit light of a different colour.
- the emission wavelengths of organic dyes are usually fine-tuned to emit light of longer wavelength by incorporation of an electron sink within the molecule that allows for delocalization of p electrons along the unsaturated chain.
- NIR dyes have been developed for many years for use in high technology fields, just a handful of them have found use for in vivo applications.
- Optical imaging in particular fluorescence offers several advantages that make it a powerful molecular imaging approach, both in the research and clinical settings. Specifically, optical imaging, besides being fast, safe, cost effective and highly sensitive, can be tailored for diagnostic as well as therapeutic outcomes.
- the organic dyes typically used as imaging reporters are amenable to design modifications through various linker chemistries to incorporate one or more targeting motifs. Fluorescence imaging is translational from the preclinical stage in small animals to human subjects as the same agent can be used without modifying the biological target. While bioluminescence has the sensitivity it is not translatable from preclinical small animal imaging to humans.
- the luciferin/luciferase based system cannot be multiplexed to interrogate multi mode based mechanism of binding to cell surface or of receptors in tumours for example in oncology applications. Fluorescence based methods are thus a natural choice to bridge the translation of imaging reagents used concurrently with the established PET, SPECT MRI and X-ray methods as the optical reporter dyes are amenable via multiple linker chemistry to carry similar or different recognition motifs.
- Molecular imaging involves the use of a “molecular” probe or agent that selectively targets a particular cellular receptor, nucleic acid sequences of a gene, amino acid sequences and post translational motifs within a protein, epigenetic modifications, cellular function and pathways, with the absence, presence or level of the specific target being indicative of a particular disease state.
- NIR fluorescent dyes have played a critical role in the optical imaging field, allowing it to become an increasingly important contributor to imaging science.
- the design of fluorescent dyes for in vivo applications needs to incorporate several important criteria including (1) water solubility, (2) structural and chemical stability, (3) NIR fluorescence, (4) high quantum yield and last but, not least (5) a functional group for bioconjugation.
- the cyanine family of dyes have been the preferred class as they provide the wavelength range for in vivo fluorescence excitation and emission not compromised by the optical properties of the tissue of interest.
- Hemoglobin has a strong absorption at wavelengths lower than 600 nm and significant background fluorescence from endogenous biomolecules can be detected up to 650 nm.
- the heptamethine cyanine dyes which absorb and emit beyond 750 nm, are classified as near infrared (NIR) dyes and are preferred labels for in vivo imaging as near infrared light can overcome the biological optical interference limitations by penetrating more deeply into tissue, because light scattering decreases with increasing wavelength.
- NIR near infrared
- Cyanine dyes are characterized as possessing two heterocyclic moieties, acting as both electron donors and acceptors, and are joined by a single or odd of number of methine groups in which (n+l) 2 electrons are distributed over n atoms producing a delocalized cation across the methine chain. This unique characteristic gives cyanine dyes a wider range of absorption than any other known class of dyes. A great number of synthetic cyanines are known to absorb between the visible and infrared regions of the electromagnetic spectrum. In addition, cyanines exhibit narrow absorption bands and high extinction coefficients.
- cyanine dyes Due to these properties, cyanine dyes have been extensively employed in various applications such as photographic processes, laser printing, nonlinear optical materials, and more recently fluorescent probes for biomolecular labelling.
- US 5,571,388 discloses exemplary methods of identifying strands of DNA by means of cyanine dyes. More recently, they have been used for optical imaging of dye- labelled biomolecules, either in vivo or in vitro (U.S. Patent No. 7,597,878, others).
- Cyanine dyes are the preferred labels in biological applications because, among other reasons, many of these dyes fluoresce in the near-infrared (NIR) region of the spectrum (600-1000 nm).
- NIR near-infrared
- cyanine dyes include, for example: 1) strong absorption cross sections and ability to fluoresce after excitation; 2) they do not rapidly bleach under a fluorescence microscope or plate reader excitation sources; 3) the derivatives are amenable as effective coupling reagents without loss of photochemical properties; 4) many structures and synthetic procedures have been developed over the last sixty years, and the class of dyes are versatile reagents; 5) cyanine dyes are relatively small (a typical molecular weight is about 1,000 daltons), so they do not cause appreciable steric interference in a way that might reduce the ability of a labelled biomolecule to reach its binding site or carry out its function and 6) when appropriately derivatized are not pH sensitive.
- cyanine dyes have a number of disadvantages, such as chemical instability in the presence of certain reagents that are commonly found in bioassays.
- reagents include ammonium hydroxide, dithiothreitol (DTT), primary and secondary amines, and ammonium persulfate (APS).
- DTT dithiothreitol
- APS ammonium persulfate
- some cyanine dyes lack the thermal stability and photostability that is necessary for biological applications such as DNA sequencing and genotyping. Besides photostability, which arises due to the cis trans summarization or disruption of the extended conjugation, aqueous solubility and charge modification are sometimes needed to derive superior biomedical applications.
- the photopoiymerizabie composition comprises at least one ethylemcally unsaturated monomer capable of free radical initiated addition polymerization and an initiator system activatable by actinic radiation, wherein said initiator system comprises a hexaarylbisimidazole, a coinitiator, and a sensitizer.
- the present application provides a fluorescent dye of formula A or a salt thereof, wherein
- Z is selected from the group consisting of NR and NR R ;
- Q is independently H or selected from the groups a), b) and c) consisting of: a) Halide selected from Cl, Br, I; R 19 U, -OR 19 U, -SR 19 U and -NR 19 R 20 U, wherein R 19 is a single bond; or wherein R 19 and R 20 each independently may be an optical properties modifying group, and are independently selected from the group consisting of: H, linear and branched, non-cyclic and cyclic, substituted and unsubstituted Ci -2 o alkyl, wherein the said alkyl group can be single or multiple substituted by a homocyclic or heterocyclic C 5 -, CV or C 7 aromatic ring which can be substituted by a linear or branched Ci-C 6 alkyl group; and homocyclic and heterocyclic 5-, 6- and 7-membered aromatic rings which can be substituted by a linear or branched Ci-C 6 alkyl group, wherein preferably one of R 19 and R 20 is not aromatic in case of -
- R 19 , -OR 19 , -SR 19 and -NR 19 R 20 wherein R 19 and R 20 each independently may be an optical properties modifying group and are independently selected from the group consisting of: H, linear and branched, non-cyclic and cyclic, substituted and unsubstituted C l-20 alkyl, wherein the said alkyl group can be single or multiple substituted by a homocyclic or heterocyclic 5-, 6- or 7-membered aromatic ring which can be substituted by a linear or branched Ci-C 6 alkyl group; and homocyclic and heterocyclic 5-, 6- and 7-membered aromatic rings which can be substituted by a linear of branched Ci-C 6 alkyl group, wherein preferably one of R 19 and R 20 is not aromatic in the case of -NR 19 R 20 ; -(CH 2 -0-CH 2 ) x CH 2 - wherein x is an integer from 1 to 50; or wherein R 19 and R 20 , together with the group consist
- R 1 and R 2 are absent, H or independently selected from the group consisting of: a) linear and branched, non-cyclic and cyclic, substituted and unsubstituted Ci -2o alkyl, wherein the said alkyl group can be single or multiple substituted by a homocyclic or heterocyclic 5-, 6- or 7-membered aromatic group which can be substituted by a linear or branched Ci-C 6 alkyl group; homocyclic and heterocyclic 5-, 6- and 7-membered aromatic rings which can be substituted by a linear of branched Ci-C 6 alkyl group; and - (CH 2 -0-CH 2 ) X CH 2 - wherein x is an integer from 1 to 50,
- R 23 is selected from the group: linear and branched, non-cyclic and cyclic, substituted and unsubstituted Ci -2o alkyl, wherein the said alkyl group can be single or multiple substituted by a homocyclic or heterocyclic C5-, G,- or G-aryl group which can be substituted by a linear or branched Ci-C 6 alkyl group; homocyclic and heterocyclic 5-, 6- and 7-membered aromatic rings which can be substituted by a linear or branched Ci- G alkyl group; -(CH 2 -0-CH 2 ) x CH 2 - wherein x is an integer from 1 to 50; and L is a linker which can form a covalent bond with a targeting agent,
- R U wherein R is a single bond; or wherein R is selected from the group: linear and branched, non-cyclic and cyclic, substituted and unsubstituted Ci -2o alkyl, wherein the said alkyl group can be single or multiple substituted by a homocyclic or heterocyclic 5-, 6- or 7-membered aromatic group which can be substituted by a linear or branched Ci-C 6 alkyl group; homocyclic and heterocyclic 5-, 6- or 7-membered aromatic rings which can be substituted by a linear or branched Ci-C 6 alkyl group; -(CH 2 -0-CH 2 ) x CH 2 - wherein x is an integer from 1 to 50; and U is a physiochemistry modifying group selected from the group consisting of: -(CH 2 ) m S0 3 ⁇ -(CH 2 ) m C(0)0 ⁇ -(CH 2 ) m P(0)0 2 2 - -(CH 2 ) m
- R 17 and R 18 are independently H or selected from the group consisting of: a) linear and branched, non-cyclic or cyclic, substituted and unsubstituted Ci -2o alkyl, wherein the said alkyl group can be single or multiple substituted by a homocyclic or heterocyclic 5-, 6- or 7-membered aromatic group which can be substituted by a linear or branched Ci-C 6 alkyl group; homocyclic and heterocyclic 5-, 6- and 7-membered aromatic rings which can be substituted by a linear or branched Ci-C 6 alkyl group, wherein preferably one of R 17 and R 18 is not aromatic; and -(CH 2 -0-CH 2 ) x CH 2 - wherein x is an integer from 1 to 50,
- R 24 is selected from the group: linear and branched, non-cyclic and cyclic, substituted and unsubstituted Ci -2o alkyl, wherein the said alkyl group can be single or multiple substituted by a homocyclic or heterocyclic 5-, 6- or 7-membered aromatic group which can be substituted by a linear or branched Ci-C 6 alkyl group; homocyclic and heterocyclic 5-, 6- or 7-membered aromatic groups which can be substituted by a linear of branched Ci-C 6 alkyl group, wherein preferably one of R 17 and R 20 is not aromatic; -(CH 2 -0-CH 2 ) x CH 2 - wherein x is an integer from 1 to 50; and L is a linker which can form a covalent bond with a targeting agent,
- R U wherein R is a single bond; or wherein R is selected from the group: linear and branched, non-cyclic and cyclic, substituted and unsubstituted Ci -2o alkyl, wherein the said alkyl group can be single or multiple substituted by a homocyclic or heterocyclic 5-, 6- or 7-membered aromatic group which can be substituted by a linear or branched Ci-C 6 alkyl group; homocyclic and heterocyclic 5-, 6- or 7-membered aromatic groups which can be substituted by a linear of branched Ci-C 6 alkyl group, wherein preferably one of R 17 and R 18 is not aromatic; -(CH 2 -0-CH 2 ) x CH 2 - wherein x is an integer from 1 to 50; and U is a physiochemistry modifying group selected from the group consisting of: -(CH 2 ) m S0 3 >(CH 2 ) m C(0)0-(CH 2 ) m NH 2 ;
- a 6 , A 7 , A 8 , A 9 , A 10 , A 11 , A 12 , and A 13 are C, N, or and either:
- indol system can comprise a total of 1 N atoms, and which azaindol system can comprise a total of 2 N atoms;
- R 3 , R 4 , R 5 , R 6 , R 7 , R 8 R 9 R 10 are independently H or selected from the group consisting of:
- R 25 is selected from the group: linear and branched, non-cyclic and cyclic, substituted and unsubstituted Ci -2 o alkyl, wherein the said alkyl group can be single or multiple substituted by a homocyclic or heterocyclic 5-, 6- or 7-membered aromatic group which can be substituted by a linear or branched C 1 -C 6 alkyl group; homocyclic and heterocyclic 5-, 6- or 7-membered aromatic groups which can be substituted by a linear of branched C 1 -C 6 alkyl group; -(CH 2 -0-CH 2 ) x CH 2 - wherein x is an integer from 1 to 50; and L is a linker which can form a covalent bond with a targeting agent, and
- R U and OR U wherein R is a single bond; or wherein R is selected from the group: linear and branched, non-cyclic and cyclic, substituted and unsubstituted Ci -2 o alkyl, wherein the said alkyl group can be single or multiple substituted by a homocyclic or heterocyclic 5-, 6- or 7-membered aromatic group which can be substituted by a linear or branched Oi-Ob alkyl group; homocyclic and heterocyclic 5-, 6- or 7-membered aromatic groups which can be substituted by a linear or branched Oi-Ob alkyl group; -(CH 2 -0- CH 2 ) X CH 2 - wherein x is an integer from 1 to 50; and U is a physiochemistry modifying group selected from the group consisting of: -(CH 2 ) m S0 3 ,-(CH 2 ) m C(0)0 , (CH 2 ) m P(0)0 2 2 - -(CH 2 -
- a 6 , A 7 , A 8 , A 9 , and A 10 , A 11 , A 12 , A 13 are C, N, or and form a 6-membered aromatic ring which together with the pyrrolin derived ring to which they are attached form an indol or an azaindol system, and to which indol or azaindol system a further 6-membered ring is annulated which is formed by at least two of the substituents R 3 , R 4 , R 5 , R 6 , or R 7 , R 8 R 9 R 10 , resulting in a trinuclear ring in which 1, 2 or 3 C atoms may be replaced by N or + N and which are substituted by R 11 , R 12 , R 13 , R 14 , R 15 , R 16 ;
- R 11 , R 12 , R 13 , R 14 , and R 15 , R 16 are independently H or selected from the group consisting of:
- R 26 is selected from the group: linear and branched, non-cyclic and cyclic, substituted and unsubstituted Ci -2 o alkyl, wherein the said alkyl group can be single or multiple substituted by a homocyclic or heterocyclic C 5 -, G,- or G-aryl group which can be substituted by a linear or branched C 1 -C 6 alkyl group, homocyclic and heterocyclic C 5 -, G,- or G-aromatic groups which can be substituted by a linear or branched C 1 -C 6 alkyl group; -(CH 2 -0-CH 2 ) x CH 2 - wherein x is an integer from 1 to 50; and L is a linker which can form a covalent bond with a targeting agent,
- R U and OR U wherein R is a single bond; or wherein R is selected from the group: linear and branched, non-cyclic and cyclic, substituted and unsubstituted Ci -2 o alkyl, wherein the said alkyl group can be single or multiple substituted by a homocyclic or heterocyclic 5-, 6- or 7-membered aromatic group which can be substituted by a linear or branched Ci-C 6 alkyl group; homocycbc and heterocyclic 5-, 6- or 7-membered aromatic groups which can be substituted by a linear of branched Ci-C 6 alkyl group; - (CH 2 -0-CH 2 ) X CH 2 - wherein x is an integer from 1 to 50; and U is a physiochemistry modifying group selected from the group consisting of: -(CH 2 ) m S0 3 ,-(CH 2 ) m C(0)0 , and d) -(CH 2 ) m P(0)0 2
- X and Y are selected from the group consisting of:
- R and R are each independently selected from H, unsubstituted and substituted linear or branched, cyclic or non-cyclic Ci-C 6 alkyl;
- E and E’ are independently selected from H, unsubstituted and substituted linear or branched, cyclic or non-cyclic C 1 -C 6 alkyl.
- the compound according to formula A contains at least 1 linker and/or 1 physiochemistry modifying group as defined in the context of the present application.
- R 19 in -OR 19 is not H.
- R 19 in -OR 19 is not H in all compounds according to formula A.
- linkers L are selected from the group consisting of: -NH 2 , -OH, -SH, -C(0)0 , C(0)Cl, -(C0)0(C0)R 27 , -C(0)NHNH 2 , -C(0), -C(0)0R 28 , wherein R 27 is selected from the group consisting of H, alkyl and aryl; wherein R 28 is derived from substituted and unsubstituted N-hydroxysuccinimide, substituted and unsubstituted N-hydroxysulfosuccinimide, nitrophenol, fluorophenol each bound via -0-; azide N 3 , -NCO, -NCS, -CHO, -COCH 2 I, phosphoramidityl, phthalamidyl, maleimide, an alkyne group in particular -CoCR 31 wherein R 31 is H or a Ci-Cg alkyl group, sul
- Fig. la-b shows absorption and fluorescence spectra, and quantum yield QY of Compound I
- Fig. 2a-b shows absorption and fluorescence spectra
- Fig. 3a-b shows absorption and fluorescence spectra, and QY of Compound III
- Fig. 4a-b shows absorption and fluorescence spectra
- Fig. 5a-b shows absorption and fluorescence spectra
- Fig. 6a-b shows absorption and fluorescence spectra
- Fig. 7a-b shows absorption and fluorescence spectra
- Fig. 8a-b shows absorption and fluorescence spectra
- Fig. 9a-b shows absorption and fluorescence spectra
- Fig. 10 Three representative mice bearing an established 4Tl-!uc2 tumours implanted subcutaneously into the right flank were injected with the indicated imaging agent (a) Mice were imaged by IVIS Spectrum to show tumour localization and (b) NIR fluorescence images to show specific biomarker detection, after intravenously receiving 0.7 nmol of antibody conjugate
- Fig. 11 shows NIR fluorescence images of 4Tl-luc2 tumour bearing mice at the indicated time points after intravenous injection of probe XXI, IntegriSenseTM 750, and RGD-ICG.
- Fig. 12 shows the optimal background/noise ratio calculated from the region of interest of 4T1 tumour bearing mice (a) at 2h post injection of probe XXI and (b) 24h post injection of Integri S ens eTM 750
- Fig. 13 shows (a) I.V. catheter injection in a 30 kg dog 6h before surgery with 180 nmol/kg of probe XXI, and (b) localization of mastocytoma tumour in dog’s right leg
- Fig. 14 shows (a) fluorescence image-guided surgical procedure of mastocytoma tumour resection.
- a mastocytoma tumour (solid arrow) is clearly identified by a rim around the tumor in vivo, 6h after injection of probe XXI.
- Normal tissue (dashed arrow) shows negligible background uptake of probe XXI.
- the enhanced ability to visualize tumor margins in fluorescence image-guided surgery led to more complete resection of the tumor (round dot arrow), and (b) shows occult malignant lesion.
- Fig. 15 shows (a) no apparent fluorescence from residual tumour could be observed after the operation, and (b) after resection carried out under the guidance of fluorescent light and slicing of the same specimen, the rim around the tumor can be visualized ex vivo
- Fig. 16 shows (a) I.V. catheter injection in a 33 Kg dog 10 h before surgery with 92 nmol/kg of probe XXI, and (b) localization of mastocytoma tumour in dog’s nose
- Fig, 17 shows (a) fluorescence image-guided surgical procedure of dog’s mastocytoma tumour and (b) after resection carried out under the guidance of fluorescent light and slicing of the same specimen, the rim around the tumor can be visualized ex vivo.
- Fig. 18 shows (a) cryogenic tissue damage with dye VI, the cells at the site of focal dry-ice treatment showed strong fluorescence signal whereas no signal was obtained from the viable cells, and (b) total photon flux of treated cells at different concentrations
- Fig. 19 shows (a) cryogenic tissue damage with dye XIV, fluorescence of the dye XIV showed strong accumulation of fluorescence at the site of focal dry -ice treatment in the cryogenic tissue, (b) total photon flux of treated tissue at different concentrations
- Fig. 20 shows the measured signal as a function of time post injection.
- Fig. 21 shows the signal and the control as a function of time.
- Fig. 22 shows the ratio of signal to control as a function of time
- Fig. 23 shows the multi-well plate and the level of fluorescence.
- Fig. 24 shows the fluorescence spectra of Compound VIII and Compound VI.
- the dyes according to formula A can contain various substituents in various positions.
- the person skilled in the art is aware of some principle differences between these substituents, according to their chemical properties and to the impact on the physical and chemical properties of the respective dye in which they are present.
- the skilled artisan will differentiate between the following types of substituents:
- Substituents of this type are attached in position Q of the dye.
- these substituents are attached to the conjugated double bonds responsible for the optical properties and will, hence, influence them.
- these substituents are inorganic or organic groups, which are known to the person skilled in the art as modulating optical properties in dyes having the structural characteristics of the dyes of the present application, in particular a conjugated double bond system.
- optical properties include: absorption, fluorescence, fluorescence quantum yield, stokes shift, lifetime, photostability and further properties known to the person skilled in the art.
- a fluorescence modulation is a change in the emission wavelength of a dye containing such fluorescence modifying substituent, with respect to the dye not containing the fluorescence modifying substituent.
- substituents include: Cl, Br; I; R 19 , -OR 19 , -SR 19 and -NR 19 R 20 wherein R 19 and R 20 are independently selected from the group consisting of: H, linear and branched, non-cyclic and cyclic, substituted and unsubstituted Ci_ 2 o alkyl, wherein the said alkyl group can be single or multiple substituted by a homocyclic or heterocyclic 5-, 6- or 7-membered aromatic ring which can be substituted by a linear or branched Ci-C 6 alkyl group; and homocyclic and heterocyclic 5-, 6- and 7-membered aromatic rings which can be substituted by a linear or branched Ci-C 6 alkyl group.
- R 19 and/or R 20 which is an organic residue in a substituent of the heterocycle being part of the conjugated double bond system, but of course applies to all other positions and substituents in the molecule which have been defined in connection with the dyes according to A, in the general and all preferred embodiments, to which an optical properties modifying substituent can be attached and/or at which position the substituent has an impact on the optical properties.
- an optical properties modifying group as defined beforehand may also contain a physiochemistry modifying group and/or a linker, see below.
- Examples for preferred optical properties modifying groups include: Cl, Br, I; 1- cyclohexylpiperazine, phenyl; -O-phenyl; -S-phenyl; -N(H)-phenyl; and wherein each of the groups phenyl, -O-phenyl, S-phenyl, -N(H)-phenyl can be single or multiple substituted by Ci- Ce alkyl; and wherein the phenyl group can be substituted by a physiochemistry modifying group U selected from the group consisting of: -(CH 2 ) m S0 3 ,-(CH 2 ) ni C(0)0 , -(CH 2 ) m P(0)0 2 2 - (CH 2 ) m NR 2 — (CH 2 ) m NH 2 ; -(CH 2 ) m NHR 32 ; (CH 2 ) m NR 32 R 33 wherein m is an integer from 0 to 6, i.e.
- R 32 , R 33 is an alkyl group having from 1 - 12, preferably 1 - 8, i.e. 1, 2, 3, 4, 5, 6, 7 and 8; more preferably 1 - 4 C atoms, in particular methyl or ethyl;
- the above groups are preferred in combination with the general, preferred, and most preferred embodiments for the other substituents Z, Q, R'-R 30 .
- Substituents of this type have an impact on various properties of the dye. These properties are in particular: solubility of the dye, stability of the dye, and, as the case may be, other properties known to the person skilled in the art. Thus, in particular these substituents render the respective dye more water soluble or more dispersible, in particular in media for administration.
- a physiochemistry modifying group can increase binding specificity, increase or decrease net molecular charge, decrease immunogenicity or toxicity, or modify cellular uptake, pharmacokinetic or biodistribution profiles, compared to the unmodified bioconjugate targeting or imaging agents.
- Further effects of physiochemistry modifiers may be enhancement of the binding selectivity of the targeting agent for receptors on the cell surface, negatively charged, apoptotic cell surfaces over other negatively charged endogenous cell surfaces, reduction of the nonspecific cell membrane permeability of the targeting agent, and reduction of nonspecific tissue accumulation of the targeting agent when administered to a live animal.
- the physiochemistry modifiers can have a pronounced impact on in vivo biodistribution and cleareance, in particular when modulating solubility.
- physiochemistry modifiers are functional groups which are known to the person skilled in the art as having an influence on solubility.
- Examples include the groups -SCfy, - wherein m is an integer from 0 to 6, and wherein R 32 , R 33 is an alkyl group having from 1 - 12, preferably 1 - 8, more preferably 1 - 4 C atoms, in particular methyl or ethyl; and wherein in case of -(CH 2 ) m NH 2 ; -(CH 2 ) m NHR 32 ; -(CH 2 ) m NR 32 R 33 the N atom may be bond to a further substituent R 34 to form a quaternary N atom, and wherein R 34 is in all the above cases independently selected from H, and an alkyl group having from 1 - 12, preferably 1 - 8, more preferably 1 - 4 C atoms, in particular methyl or ethyl.
- -(CH 2 ) m NH 2 -(CH 2
- substituent R 34 is preferably identical with the other substituents, i.e. at least one of them if R and R are different, or with both in case R and R are the same.
- R 32 and R 33 and R 34 are identical and form a group -(CH 2 ) m N + R 32 R 33 R 34 , or a group -(CH 2 ) m N TT 3 , with m being an integer from 0 to 6, and wherein R , R , and R are an alkyl group having from 1 - 12, preferably 1 - 8, more preferably 1 - 4 C atoms, in particular methyl or ethyl.
- the above-named functional groups can be attached directly to a C or N atom which is part of the basic structure of the dye according to A, or these groups can be attached to such N or C atom via an alkyl group, as expressed by the formulae -(CH 2 ) m S0 3 ,-(CH 2 ) m C(0)0 ,- (CH 2 ) m P(0)0 2 2 -(CH 2 ) m NR 2 — (CH 2 ) m NH 2 ; -(CH 2 ) m NHR 32 ; (CH 2 ) m NR 32 R 33 wherein m is an integer from 0 to 6, i.e.
- R , R , and R are an alkyl group having from 1 - 12, preferably 1 - 8, i.e. 1, 2, 3, 4, 5, 6, 7 and 8; more preferably 1 - 4 C atoms, in particular methyl or ethyl; or these groups can be attached to a substituent of a C or a N atom which is part of the basic structure of the dye, as expressed by -R 19 U, -OR 19 U, -SR 19 U and - NR 19 UR 20 wherein R 19 and R 20 are independently selected from the group consisting of: H, linear and branched, non-cyclic and cyclic, substituted and unsubstituted Ci -2 o alkyl, wherein the said alkyl group can be single or multiple substituted by a homocyclic or heterocyclic 5-, 6- or 7- membered aromatic ring which can be substituted by a linear of branched C1-C6 alkyl group; and homocyclic and heterocycl
- the groups attached to a C or N atom of the dye, on the one hand side, and to the physiochemistry modifying group, on the other hand side, are also referred to as“spacer” or “spacer group” in the present context.
- the above definition is not limited to R 19 which is an organic residue in a substituent of the heterocycle being part of the conjugated double bond system, but of course applies to all other positions and substituents in the molecule which have been defined in connection with the dyes according to S, in the general and all preferred embodiments, to which a physiochemistry modifying group can be attached.
- Substituents of this type serve to link the dye to the targeting agent.
- these linkers are functional groups which are known to the person skilled in the art as being capable of linking a molecule to another molecule in a chemical reaction, under formation of a“linking group” between the dyes of the subject matter of the present application and a targeting agent.
- the chemical reaction preferably forms a covalent bond between the dye and the targeting agent.
- linkers include the groups -NH 2 , - OH, -SH, -C(0)0 , -C(0)Cl, -(C0)0(C0)R 27 wherein R 27 is selected from the group consisting of H, alkyl and aryl; -C(0)NHNH 2 , -C(0)0R 28 wherein R 28 is derived from substituted and unsubstituted N-hydroxysuccinimide, substituted and unsubstituted N-hydroxysulfosuccinimide, nitrophenol, fluorophenol each bound via -0-; azide NT.
- linkers examples include sulfonate esters, alkyl halides, acyl halides, propargylglycine, a pentanoyl group (like in pentanoyl chloride), pentynoic acid, propargylic acid, 6-aminobenzo[if]thiazole-2-carbonitrile, 6- hydroxy benzoyl thiazole-2-carbonitrile. a 1 ,2-aminothiol group, in particular L-cysteine or D- cysteine.
- linkers can react with complementary groups present on the targeting agent in reactions known as such to the skilled person.
- R 23 L is selected from the group: linear and branched, non-cyclic and cyclic, substituted and unsubstituted Ci -2 o alkyl, wherein the said alkyl group can be single or multiple substituted by a homocyclic or heterocyclic C5-, C 6 - or C--aryl group; homocyclic and heterocyclic 5-, 6- or 7-membered aromatic rings; -(CH 2 -0-CH 2 ) x CH 2 - wherein x is an integer from 1 to 50; and L is a linker which can form a covalent bond with a targeting agent.
- the groups attached to a C or N atom of the dye, on the one hand side, and to the linker, on the other hand side, are also referred to as“spacer” or“spacer group” in the present context.
- R 23 which is an organic residue in a substituent of the heterocycle being part of the conjugated double bond system, but of course applies to all other positions and substituents in the molecule which have been defined in connection with the dyes according to S, in the general and all preferred embodiments, to which a solubility modifying group can be attached.
- “Click” chemistry provides one possible way for linking the fluorescent dyes of the subject matter of the present application to targeting agents.
- “click chemistry” can be used to connect the dye to the targeting agent via a chemical reaction of the linker.
- “Click” chemistry uses simple, robust reactions, such as the copper-catalyzed cycloaddition of azides and alkynes, to create intermolecular linkages.
- Another novel thiol-based“click” reaction involves the efficient condensation between the cyano group of 2-cyano-6-aminobenzothiazole (CBT) (or 2-cyano-6- hydroxybenzothiazole) and l,2-aminothiol group of L-cysteine (or D-cysteine) to yield a thiazole functionality, which can be controlled by pH, reduction and enzyme reported by White, et al. J. Am. Chem. Soc. 85 (1963). To date, this click condensation reaction has been successfully employed to design smart optical imaging probes.
- CBT 2-cyano-6-aminobenzothiazole
- L-cysteine or D-cysteine
- A cites other substituents, which do not have any of the above effects, or only to a minor extent. These other type substituents may e.g., be present in the molecule due to the availability of starting compounds, or they may facilitate the synthesis of the respective dye, or they are present due to other reasons known to the person skilled in the art. Groups, which do not have the above effects and thus belong into the present group, are known to the skilled person.
- the molecules of the present application provide various possibilities for the attachment of various substituents, which do not or not substantially change the molecules’ properties. It is contemplated that substituent Q is an exception to this, due to its proximity to the conjugated double bond system in the substituents Q, meaning that a modification of Q may have an impact on the optical properties of the molecule. This, however, depends on each single case.
- a physiochemistry modifying group and/or a linker may be attached to a large number of positions, sometimes in practice even any position, in the molecules A which are synthetically accessible and which does not negatively affect the purpose of the respective substituent.
- a linker serving to attach a targeting agent to the dye
- inert groups like e.g., alkyl groups of various lengths
- the dye still lends itself for its intended purposes with respect to its analogue not substituted in the respective position, as important properties like the solubility and/or the optical properties are not or not substantially effected.
- the skilled artisan is aware that a large number of groups can be attached to various sites without (substantially) changing the molecules’ properties (namely physiochemistry, solubility, optical properties, e.g., fluorescence properties).
- “R” is a single bond (e.g., in connection with R U, where it is quoted that R ,“R U is a single bond”)
- this relates to the case that the group U is directly connected to the respective site of the dye via a chemical bond, in general via a single bond.
- the skilled person is aware that he present application includes not only the case that the 1 linker L (generally attached via a spacer group) or 1 physiochemistry modifying group U (which may be attached via a spacer group or not) is/are present, but also to the case that 2, 3, 4 or more groups U and 2, 3, 4 or more groups L are present in the dye. In a preferred embodiment, 1 or 2 groups L are present in the dyes according to the subject matter of the present application.
- the dyes according to the application should be inert and stable under physiological conditions, as a reaction during monitoring or diagnosing a disease is not desirable, in particular when monitoring or diagnosing is carried out in vitro. This means that it should be avoided to prepare dyes carrying reactive groups under the conditions of monitoring/diagnosis (i.e. that these groups undrgo chemical reactions when exposed to the typical conditions applied during the monitoring or the diagnosis process), in particular physiological conditions.
- the groups attached to the dyes according to the present subject matter if not serving to modulate physiochemical properties and/or optical properties, are inert groups which show only a low reactivity at maximum, and which in general do not affect the physiochemical properties and/or optical properties.
- these groups serve as a “spacer”, holding a physiochemical properties modulating group and/or a linker in or at the end of their chain.
- a linker a respective linker attached to the chain (where the chain is often linear and branched, non-cyclic and cyclic, substituted and unsubstituted Ci -2 o alkyl, wherein the said alkyl group can be single or multiple substituted by a homocycbc or heterocyclic 5-, 6- or 7-membered aromatic ring which can be substituted by a linear of branched Ci-C 6 alkyl group; and homocycbc and heterocyclic 5-, 6- and 7-membered aromatic rings which can be substituted by a linear of branched Ci-C 6 alkyl group, or a group -(CH 2 -0- CH 2 ) X CH 2 - wherein x is an integer from 1 to 50) must not be too close to the basic structure, in order to avoid steric interactions
- a spacer group must show no or only a low chemical reactivity (which also applies for the basic structure of the dye) and must not influence in particular the optical properties of the resulting dye, or only to a minor extent which has no practical relevance. Accordingly, a huge amount of spacers having various alkyl chain lengths and/or various sizes and various natures of the aromatic group may be used in the context of the present application, which do not or only minimally alter the optical properties of the dye.
- solubility is a component of physiochemical properties, and the solubility of a dye may change with the length and nature of the spacer (alkyl, aralkyl or aromatic group, alkyleneoxy group; chain length in case of alkyl, and ring size and presence of heteroatoms in an aromatic ring), these parameters may also affect physiochemical properties.
- Alkyleneoxy groups enhance water-solubility of a molecule in general, where aromatic groups reduce water- solubility, in general.
- the effect of these parameters, in general will only be observed to a lesser extent than for physiochemical property modulating groups.
- alkyl refers to an aliphatic saturated hydrocarbon group which may be linear or branched, including methyl (Ci alkyl), ethyl (C 2 alkyl), n-propyl, iso-propyl (G alkyl), n-butyl, iso-butyl, sec.-butyl and tert.-butyl (C 4 alkyl), n-pentyl (amyl), 2-pentyl (sec-pentyl), 3-pentyl; 2- methylbutyl, 3-methylbutyl (iso-pentyl or iso-amyl), 3-methylbut-2-yl, 2-methylbut-2-yl; 2,2- dimethylpropyl (neopentyl) (C 5 alkyl), a hexyl group (G, alkyl) including all isomers, a heptyl group (C 7 alkyl) including all isomers, an octyl group (G alkyl),
- alkyl also refers to an aliphatic saturated cyclic hydrocarbon group, which may have alkyl substituents. Examples include cyclopropyl (C 3 cycloalkyl), cyclobutyl (C 4 cycloalkyl), cyclopentyl (C5 cycloalkyl), cyclohexyl (C 6 cycloalkyl), cycloheptyl (C 7 cycloalkyl), and cyclooctyl (C 8 cycloalkyl). Each hydrogen of a cycloalkyl carbon may be replaced by an alkyl substituent.
- phenyl refers to the group -C 6 H 5 as known to the person skilled in the art.
- the aromatic ring of the phenyl group may be substituted 1 or 2 times by C1-C4 alkyl and/or 1 or 2 times by Cl, Br. I.
- aromatic groups are known to the person skilled in the art, who is also aware that typical representatives have 5, 6 or 7 members in its cycle, and of the heteroatoms which may be present.
- Typical examples for heteroatoms in the context of the present application are N, O and A. In the context of the present application, N and O are preferred.
- Non-limiting examples include phenyl, pyridyl (6-membered), pyrrol, furyl, thiophen (5-membered), cycloheptatrienyl (7-membered).
- the aromatic heterocycle can be connected to the respective place in the dye via the heteroatom or via a C-atom.
- a homocyclic 6-membered aromatic group is phenyl of pyridyl, preferably phenyl.
- Aryl or“Ar” or“aromatic group” refers to a monovalent aromatic carbocyclic group of from 5 to 18 carbon atoms having a single ring such as C6 in phenyl or anion such as C5 cyclopentadienyl anion or a ring system having multiple condensed rings such as those in anthracenyl, napthyl, phenanthrenyl, the condensed rings may be bridged by a transition atom or ion such as iron with two cyclopentadienyl anions in ferrocene, the condensed rings may or may not be aromatic, provided that the point of attachment is through an atom of an aromatic ring such as dihydroindolyl, dihydrobenzthiazolyl and other partially hydrogenated aromatic groups.
- aryl substituents that are defined by groups obeying Huckels law of 4n+2 pi electrons (n being an integer)
- aryl groups can optionally be substituted with from 1 to 5 substituents, or from 1 to 3 substituents,
- Amino refers to the group— NH 2 .
- Substituted amino refers to the group— NRR where each R is independently selected from the group consisting of hydrogen, Ci-Cg alkyl, which can be substituted or unsubstituted, C5-C7 cycloalkyl which can be substituted or unsubstituted, and a homocyclic 5-, 6- or 7-membered aromatic group, provided that at least one R is not hydrogen.
- Carboxyl,“carboxy” or“carboxylate” refers to— C(0)OH or salts thereof derived from C0 2
- Cyano or“nitrile” refers to the group— CN.
- Thiocyanate refers to the group— SCN.
- Halo halide or“halogen” refers to F, Cl, Br and I, preferably Cl, Br and I.
- “Hydroxy” or“hydroxyl” refers to the group— OH.
- Heteroaryl refers to an aromatic group of from 2 to 15 carbon atoms, such as from 3 to 10 carbon atoms and 1 to 10 heteroatoms selected from the group consisting of oxygen, nitrogen (referred to as aza in the application) and sulfur within the ring.
- heteroaryl groups can have a single ring (such as, pyrrole, pyridyl, imidazolyl or furyl) or multiple condensed rings in a ring system (for example as in groups such as, indolizinyl, quinolinyl, benzofuran, benzimidazolyl or benzothienyl), wherein at least one ring within the ring system is aromatic and at least one ring within the ring system is aromatic, provided that the point of attachment is through an atom of an aromatic ring.
- a single ring such as, pyrrole, pyridyl, imidazolyl or furyl
- multiple condensed rings in a ring system for example as in groups such as, indolizinyl, quinolinyl, benzofuran, benzimidazolyl or benzothienyl
- the nitrogen and/or sulfur ring atom(s) of the heteroaryl group are optionally oxidized to provide for the N-oxide (N 0), sulfmyl, or sulfonyl moieties.
- N 0 N-oxide
- sulfmyl N-oxide
- sulfonyl moieties N-oxide (N 0), sulfmyl, or sulfonyl moieties.
- This term includes, by way of example, pyridinyl, pyrrolyl, indolyl, thiophenyl, and furanyl.
- heteroaryl groups can be optionally substituted with 1 to 5 substituents, or from 1 to 3 substituents, selected from acyloxy, hydroxy, thiol, acyl, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkoxy, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted cycloalkenyl, amino, substituted amino, aminoacyl, acylamino, alkaryl, aryl, aryloxy, azido, carboxyl, carboxylalkyl, cyano, halogen, nitro, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, aminoacyloxy, oxyacylamino, thioalkoxy, substituted thioalkoxy, thioaryloxy, thio
- Haldroxylamino refers to the group— NHOH.
- N-hydroxysuccinimide is the N-hydroxy derivative of succinimide.
- substituted and unsubstituted N-hydroxysulfosuccinimide refers to the N-hydroxy derivative of succinimide which is substituted by a group -SO 3 at the 5-membered cycle.
- Z is selected from the group consisting of N, NR 17 , + NR 17 R 18 .
- Z is N or T N, NR 17 , or T NR 17 R 18.
- Z is N or T N, NR 17 , or T NR 17 R 18.
- Q is independently H or selected from the groups a), b),and c) consisting of: a) Halide selected from Cl, Br, I; R 19 U, -OR 19 U, -SR 19 U and -NR 19 R 20 U, wherein R 19 is a single bond; or wherein R 19 and R 20 may independently be an optical properties modifying group, and are independently selected from the group consisting of: H, linear and branched, non-cyclic and cyclic, substituted and unsubstituted Ci_2o alkyl, wherein the said alkyl group can be single or multiple substituted by a homocyclic or heterocyclic C 5 -, CV or C 7 aromatic ring which can be substituted by a linear or branched C 1 -C 6 alkyl group; and homocyclic and heterocyclic 5-, 6- and 7-membered aromatic rings which can be substituted by a linear or branched C1-C6 alkyl group, wherein preferably one of R 19 and R
- R 21 and R 22 may be an optical properties modifying group and are independently selected from the group consisting of: H, linear and branched, non-cyclic and cyclic, substituted and unsubstituted Ci -2 o alkyl, wherein the said alkyl group can be single or multiple substituted by a homocyclic or heterocyclic 5-, 6- or 7-membered aromatic group which can be substituted by a linear or branched Ci-C 6 alkyl group; homocyclic and heterocyclic 5-, 6- or 7-membered aromatic rings which can be substituted by a linear or branched Ci-C 6 alkyl group, wherein preferably one of R 21 and R 22 is not aromatic in case of -NR 21 R 22 ; -(CH 2 -0-CH 2 ) x CH 2 -L wherein x is an integer from 1 to 50; and L is a linker which can form a covalent
- R 19 , -OR 19 , -SR 19 and -NR 19 R 20 wherein R 19 and R 20 wherein R 19 and R 20 may independently be an optical properties modifying group and are independently selected from the group consisting of: H, linear and branched, non-cyclic and cyclic, substituted and unsubstituted Ci -2o alkyl, wherein the said alkyl group can be single or multiple substituted by a homocyclic or heterocyclic 5-, 6- or 7-membered aromatic ring which can be substituted by a linear or branched Ci-C 6 alkyl group; and homocyclic and heterocyclic 5-, 6- and 7-membered aromatic rings which can be substituted by a linear of branched Ci-C 6 alkyl group, wherein preferably one of R 19 and R 20 is not aromatic in case of -NR 19 R 20 ; -(CH 2 -0-CH 2 ) X CH 2 - wherein x is an integer from 1 to 50; or wherein R 19 and R 20
- R 19 in -OR 19 is not H. This is in particular the case if the compound according to formula A does not contain at least 1 linker and/or 1 physiochemistry modifying group as defined in the context of the present application.
- Q is independently H or selected from the groups a), b), and c) consisting of: a) halide selected from Cl, Br, I; R 19 U, -OR 19 U, -SR 19 U and -NR 19 R 20 U; wherein R 19 is a single bond; or wherein R 19 and R 20 may independently be an optical properties modifying group, and are independently selected from the group consisting of: H, linear, non-cyclic, substituted and unsubstituted Ci-i 2 alkyl, wherein the said alkyl group can be single or multiple substituted by a homocyclic 6-membered aromatic group which can be substituted by a linear or branched C 1 -C 4 alkyl group; and homocyclic 6-membered aromatic rings which can be substituted by a linear or branched C 1 -C 4 alkyl group, wherein preferably one of R 19 and R 20 is not aromatic in case of -NR 19 R 20 U; -(CH 2 -0- CH 2
- R 21 and R 22 may independently be an optical properties modifying group and are independently selected from the group consisting of: H; linear, non-cyclic, substituted and unsubstituted C 2 alkyl, wherein the said alkyl group can be single or multiple substituted by a homocyclic C 6 - aryl group which can be substituted by a linear or branched C 1 -C 4 alkyl group; -(CH 2 -0-CH 2 ) x CH 2 - wherein x is an integer from 1 to 20; and homocyclic 6-membered aromatic groups rings which can be substituted by a linear or branched C 1 -C 4 alkyl group, wherein preferably one of R and R is not aromatic in case of -NR R ; and L is a linker which can form a covalent bond with a targeting agent;
- R 19 , -OR 19 , -SR 19 and -NR 19 R 20 wherein R 19 and R 20 may independently be an optical properties modifying group and are independently selected from the group consisting of: H; linear, non-cyclic, substituted and unsubstituted Ci_i 2 alkyl, wherein the said alkyl group can be single or multiple substituted by a homocyclic C 6 - aryl group which can be substituted by a linear or branched C 1 -C 4 alkyl group; and homocyclic 6-membered aromatic groups which can be substituted by a linear or branched C 1 -C 4 alkyl group, wherein preferably one of R 19 and R 20 is not aromatic in case of -NR 19 R 20 U; -(CH 2 -0- CH 2 ) X CH 2 - wherein x is an integer from 1 to 20; or wherein R 19 and R 20 , together with the N atom to which they are attached, form a 5- or 6-membered heterocycle optionally
- R 19 in -OR 19 is not H. This is in particular the case if the compound according to formula A does not contain at least 1 linker and/or 1 physiochemistry modifying group as defined in the context of the present application.
- Q is independently H or selected from the groups a), b),and c) consisting of: a) Halide selected from Cl, Br, I; R 19 U, -OR 19 U, -SR 19 U and -NR 19 R 20 U, wherein R 19 is a single bond; or wherein R 19 and R 20 may independently be an optical properties modifying group, and are independently selected from the group consisting of: H; linear, non-cyclic, substituted and unsubstituted Ci -8 alkyl, wherein the said alkyl group can be single substituted by a homocyclic 6-membered aromatic group; and homocyclic 6- membered aromatic groups wherein preferably one of R 19 and R 20 is not aromatic in case of -NR 19 R 20 U; -(CH 2 -0-CH 2 ) X CH 2 - wherein x is an integer from 1 to 12; and U is a physiochemistry modifying group selected from the group consisting of: -(GrBfySCV
- (CH 2 ) m NR 32 R 33 wherein m is an integer from 0 to 6, and wherein R 32 , R 33 , is an alkyl group having from 1 - 12, preferably 1 - 8, more preferably 1 - 4 C atoms, in particular methyl or ethyl; and wherein in case of -(CH 2 ) m NH 2 ; -(CH 2 ) m NHR 32 ; -(CH 2 ) m NR 32 R 33 the N atom may be bond to a further substituent R 34 to form a quaternary N atom, and wherein R 34 is in all the above cases independently selected from H, and an alkyl group having from 1 - 12, preferably 1 - 8, more preferably 1 - 4 C atoms, in particular methyl or ethyl,
- R 21 and R 22 may independently be an optical properties modifying group and are independently selected from the group consisting of: H; linear, non-cyclic, substituted and unsubstituted Ci -8 alkyl, wherein the said alkyl group can be single substituted by a homocyclic 6-membered aromatic group; homocyclic 6-membered aromatic groups, wherein preferably one of R 21 and R 22 is not aromatic in case of -NR 21 R 22 ; -(CH 2 -0-CH 2 ) x CH 2 -L wherein x is an integer from 1 to 12; and L is a linker which can form a covalent bond with a targeting agent; and L is a linker which can form a covalent bond with a targeting agent;
- R 19 , -OR 19 , -SR 19 and -NR 19 R 20 wherein R 19 and R 20 may independently be an optical properties modifying group and are independently selected from the group consisting of: H; linear, non-cyclic, substituted and unsubstituted Ci -8 alkyl, wherein the said alkyl group can be single substituted by a homocyclic 6-membered aromatic group; and homocyclic 6-membered aromatic groups, wherein preferably one of R 19 and R 20 is not aromatic in case of -NR 21 R 22 ; -(CH 2 -0-CH 2 ) x CH 2 - wherein x is an integer from 1 to 12; or wherein R 19 and R 20 , together with the N atom to which they are attached, form a 6- membered heterocycle optionally containing one further heteroatom selected from O and N, wherein the heterocycle can be substituted by a linear or branched, cyclic or non cyclic Ci-C 6 alkyl group, in particular 4-cyclohex
- R 19 in -OR 19 is not H. This is in particular the case if the compound according to formula A does not contain at least 1 linker and/or 1 physiochemistry modifying group as defined in the context of the present application.
- Q is independently H or selected from the groups a), b),and c) consisting of: a) Halide selected from Cl, Br, I; R 19 U, -OR 19 U, and -NR 19 R 20 U, wherein R 19 is a single bond; or wherein R 19 and R 20 may independently be an optical properties modifying group, and are independently selected from the group consisting of: H; linear, non-cyclic, substituted and unsubstituted Ci -8 alkyl, wherein the said alkyl group can be single substituted by a homocyclic 6-membered aromatic group; and homocyclic 6-membered aromatic groups wherein preferably one of R 19 and R 20 is not aromatic in case of - NR 19 R 20 U; -(CH 2 -0-CH 2 ) X CH 2 - wherein x is an integer from 1 to 6; and U is a physiochemistry modifying group selected from the group consisting of: -(CH 2 ) m S03 ,-
- (CH 2 ) m NR 32 R 33 wherein m is an integer from 0 to 6, and wherein R 32 , R 33 , is an alkyl group having from 1 - 12, preferably 1 - 8, more preferably 1 - 4 C atoms, in particular methyl or ethyl and wherein in case of -(CH 2 ) m NH 2 ; -(CH 2 ) m NHR 32 ; -(CH 2 ) m NR 32 R 33 the N atom may be bond to a further substituent R 34 to form a quaternary N atom, and wherein R 34 is in all the above cases independently selected from H, and an alkyl group having from 1 - 12, preferably 1 - 8, more preferably 1 - 4 C atoms, in particular methyl or ethyl,
- R 21 and R 22 may independently be an optical properties modifying group and are independently selected from the group consisting of: H; linear, non-cyclic, substituted and unsubstituted Ci -8 alkyl, wherein the said alkyl group can be single substituted by a homocyclic 6-membered aromatic group; homocyclic 6-membered aromatic groups, wherein preferably one of R 21 and R 22 is not aromatic in case of -NR 21 R 22 ; -(CH 2 -0-CH 2 ) x CH 2 -L wherein x is an integer from 1 to 6; and L is a linker which can form a covalent bond with a targeting agent; and L is a linker which can form a covalent bond with a targeting agent;
- R 19 , -OR 19 , and -NR 19 R 20 wherein R 19 and R 20 may independently be an optical properties modifying group and are independently selected from the group consisting of: H; linear, non-cyclic, substituted and unsubstituted Ci -8 alkyl, wherein the said alkyl group can be single substituted by a homocycbc 6-membered aromatic group; and homocycbc 6-membered aromatic groups, wherein preferably one of R 19 and R 20 is not aromatic in case of -NR 21 R 22 ; -(CH 2 -0-CH 2 ) x CH 2 - wherein x is an integer from 1 to 6; or wherein R 19 and R 20 , together with the N atom to which they are attached, form a 6- membered heterocycle optionally containing one further heteroatom selected from O and N, wherein the heterocycle can be substituted by a linear or branched, cyclic or non cyclic Ci-C 6 alkyl group, in particular 4-cyclo
- R 19 in -OR 19 is not H. This is in particular the case if the compound according to formula A does not contain at least 1 linker and/or 1 physiochemistry modifying group as defined in the context of the present application.
- R 1 and R 2 are absent?, H or independently selected from the group:
- Ci -2 o alkyl a) linear and branched, non-cyclic and cyclic, substituted and unsubstituted Ci -2 o alkyl, wherein the said alkyl group can be single or multiple substituted by a homocycbc or heterocyclic 5-, 6- or 7-membered aromatic group which can be substituted by a linear or branched Ci-C 6 alkyl group; homocycbc and heterocyclic 5-, 6- and 7-membered aromatic rings which can be substituted by a linear of branched Ci-C 6 alkyl group; and - (CH2-0-CH 2 ) X CH 2 - wherein x is an integer from 1 to 50;
- R 23 L wherein R 23 is selected from the group: linear and branched, non-cyclic and cyclic, substituted and unsubstituted Ci -2o alkyl, wherein the said alkyl group can be single or multiple substituted by a homocycbc or heterocyclic C5-, C 6 - or C 7-aryl group which can be substituted by a linear or branched Ci-C 6 alkyl group; homocycbc and heterocyclic 5-, 6- and 7-membered aromatic rings which can be substituted by a linear or branched Ci- Ce alkyl group; -(CH 2 -0-CH 2 ) x CH 2 - wherein x is an integer from 1 to 50; and L is a linker which can form a covalent bond with a targeting agent; c) R 23 U, wherein R 23 is a single bond; or wherein R 23 is selected from the group: linear and branched, non-cyclic and cyclic, substituted and unsubstitute
- R 1 and R 2 are absent, independently H or selected from the group:
- Ci-i 2 alkyl a) linear, non-cyclic, substituted and unsubstituted Ci-i 2 alkyl, wherein the said alkyl group can be single or multiple substituted by a homocycbc C 6 - aromatic group which can be substituted by a linear or branched C 1 -C 4 alkyl group; homocycbc 6-membered aromatic rings which can be substituted by a linear or branched C 1 -C 4 alkyl group; and -(CH 2 -0- CH 2 ) X CH 2 - wherein x is an integer from 1 to 20;
- R 23 is selected from the group: linear, non-cyclic, substituted and unsubstituted Ci-i 2 alkyl, wherein the said alkyl group can be single or multiple substituted by a homocycbc C 6 - -aromatic group which can be substituted by a linear or branched C 1 -C 4 alkyl group; homocycbc G, aromatic rings which can be substituted by a linear or branched C 1 -C 4 alkyl group; -(CH 2 -0-CH 2 ) x CH 2 - wherein x is an integer from 1 to 20; and L is a linker which can form a covalent bond with a targeting agent;
- R U wherein R is a single bond; wherein R is selected from the group: linear, non- cyclic, substituted and unsubstituted Ci-i 2 alkyl, wherein the said alkyl group can be single or multiple substituted by a homocycbc 6-membered aromatic group which can be substituted by a linear or branched C 1 -C 4 alkyl group; homocycbc G, aromatic rings which can be substituted by a linear or branched C 1 -C 4 alkyl group; -(CH 2 -0-CH 2 ) x CH 2 - wherein x is an integer from 1 to 20; and U is a physiochemistry modifying group selected from the group consisting of: -(CH 2 ) m S0 3 ,-(CH 2 ) m C(0)0 , -(CH 2 ) m P(0)0 2 2 - (CH 2 ) m NR 2 — (CH 2 ) m NH 2 ; -
- R U wherein R is a single bond; or wherein R is selected from the group: linear, non-cyclic, substituted and unsubstituted Ci -8 alkyl, wherein the said alkyl group can be single substituted by a homocyclic 6-membered aromatic group; homocyclic 6- membered aromatic groups; -(CH 2 -0-CH 2 ) x CH 2 - wherein x is an integer from 1 to 12; and U is a physiochemistry modifying group selected from the group consisting of: -(CH 2 ) m S0 3 -,-(CH 2 ) m C(0)Cr, -(CH 2 ) m P(0)0 2 2 - -(CH 2 ) m NR 2
- R 1 and R 2 are absent, H or independently selected from the group:
- Ci -8 alkyl a) linear, non-cyclic, substituted and unsubstituted Ci -8 alkyl, wherein the said alkyl group can be single substituted by a homocyclic 6-membered aromatic group; homocyclic 6-membered aromatic rings; and -(CH 2 -0-CH 2 ) x CH 2 - wherein x is an integer from 1 to 6;
- R 23 is selected from the group: linear, non-cyclic, substituted and unsubstituted Ci -8 alkyl, wherein the said alkyl group can be single substituted by a homocyclic 6-membered aromatic group; homocyclic 6-membered aromatic group; - (CH 2 -0-CH 2 ) X CH 2 - wherein x is an integer from 1 to 8; and L is a linker which can form a covalent bond with a targeting agent;
- R U wherein R is a single bond; or wherein R is selected from the group: linear, non-cyclic, substituted and unsubstituted Ci -8 alkyl, wherein the said alkyl group can be single substituted by a homocyclic 6-membered aromatic group; homocyclic 6- membered aromatic groups; -(CH 2 -0-CH 2 ) x CH 2 - wherein x is an integer from 1 to 6; and U is a physiochemistry modifying group selected from the group consisting of: -(CH 2 ) m S0 3 ⁇ -(CH 2 ) m C(0)0-, -(CH 2 ) m P(0)0 2 2 - -(CH 2 ) m NR 2
- R 17 and R 18 are independently H or selected from the group consisting of:
- Ci-C 6 alkyl group can be single or multiple substituted by a homocyclic or heterocyclic 5-, 6- or 7-membered aromatic group which can be substituted by a linear or branched Ci-C 6 alkyl group; homocyclic and heterocyclic 5-, 6- and 7-membered aromatic rings which can be substituted by a linear or branched Ci-C 6 alkyl group, wherein preferably one of R 17 and R 18 is not aromatic; and -(CH 2 -0-CH 2 ) x CH 2 - wherein x is an integer from 1 to 50
- R 24 is selected from the group: linear and branched, non-cyclic and cyclic, substituted and unsubstituted Ci -2o alkyl, wherein the said alkyl group can be single or multiple substituted by a homocyclic or heterocyclic 5-, 6- or 7-membered aromatic group which can be substituted by a linear or branched Ci-C 6 alkyl group; homocyclic and heterocyclic 5-, 6- or 7-membered aromatic groups which can be substituted by a linear of branched Ci-C 6 alkyl group, wherein preferably one of R 17 and R 20 is not aromatic; -(CH 2 -0-CH 2 ) x CH 2 - wherein x is an integer from 1 to 50; and L is a linker which can form a covalent bond with a targeting agent;
- R U wherein R is a single bond; or wherein R is selected from the group: linear and branched, non-cyclic and cyclic, substituted and unsubstituted Ci -2o alkyl, wherein the said alkyl group can be single or multiple substituted by a homocyclic or heterocyclic 5-, 6- or 7-membered aromatic group which can be substituted by a linear or branched Ci-C 6 alkyl group; homocyclic and heterocyclic 5-, 6- or 7-membered aromatic groups which can be substituted by a linear of branched Ci-C 6 alkyl group, wherein preferably one of R 17 and R 18 is not aromatic; -(CH 2 -0-CH 2 ) x CH 2 - wherein x is an integer from 1 to 50; and U is a physiochemistry modifying group selected from the group consisting of: -(CH 2 ) m S0 3 -,-(CH 2 ) m C(0)0-(CH 2 ) m NH 2
- R 17 and R 18 are independently H or selected from the group consisting of:
- Ci-i 2 alkyl a) linear, non-cyclic, substituted and unsubstituted Ci-i 2 alkyl, wherein the said alkyl group can be single or multiple substituted by a homocyclic 6-membered aromatic group; homocyclic 6-membered aromatic groups which can be substituted by a linear or branched C 1 -C 4 alkyl group, wherein preferably one of R 17 and R 18 is not aromatic; - (CH 2 -0-CH 2 ) X CH 2 - wherein x is an integer from 1 to 20; and
- R 24 is selected from the group: linear, non-cyclic, substituted and unsubstituted Ci-i 2 alkyl, wherein the said alkyl group can be single or multiple substituted by a homocyclic 6-membered aromatic group which can be substituted by a linear or branched C 1 -C 4 alkyl group; homocyclic 6-membered aromatic group which can be substituted by a linear or branched C 1 -C 4 alkyl group, wherein preferably one of R 17 and R 18 is not aromatic; -(CH 2 -0-CH 2 ) x CH 2 - wherein x is an integer from 1 to 20; and L is a linker which can form a covalent bond with a targeting agent;
- R U wherein R is a single bond; or wherein R is selected from the group: linear, non-cyclic, substituted and unsubstituted Ci-i 2 alkyl, wherein the said alkyl group can be single or multiple substituted by a homocyclic 6-membered aromatic group which can be substituted by a linear or branched C 1 -C 4 alkyl group; homocyclic 6-membered aromatic groups which can be substituted by a linear or branched C 1 -C 4 alkyl group, wherein preferably one of R 17 and R 18 is not aromatic; -(CH 2 -0-CH 2 ) x CH 2 - wherein x is an integer from 1 to 20; and U is a physiochemistry modifying group selected from the group consisting of: -(CH 2 ) m S0 3 >(CH 2 ) m C(0)0 ⁇ , -(CH 2 ) m P(0)0 2 2 - -(CH 2 ) m NR 2 -
- R 17 and R 18 are independently H or selected from the group consisting of:
- R U wherein R is a single bond; or wherein R is selected from the group: linear and branched, non-cyclic and cyclic, substituted and unsubstituted Ci -8 alkyl, wherein the said alkyl group can be single substituted by a homocyclic 6-membered aromatic group; homocyclic 6-membered aromatic groups; wherein preferably one of R 17 and R 18 is not aromatic; -(CH 2 -0-CH 2 ) x CH 2 - wherein x is an integer from 1 to 12; and U is a physiochemistry modifying group selected from the group consisting of: -(CH 2 ) m S(V ,-(CH 2 ) m C(0)0 , -(CH 2 ) m P(0)0 2 2 - -(CH 2 ) m NR 2 -(CH 2 ) m NH 2 ; -(CH 2 ) m NHR 32 ;
- R 17 and R 18 are independently H or selected from the group consisting of:
- Ci -8 alkyl a) linear, non-cyclic, substituted and unsubstituted Ci -8 alkyl, wherein the said alkyl group can be single substituted by a homocyclic 6-membered aromatic group; homocyclic 6- membered aromatic groups, wherein preferably one of R 17 and R 18 is not aromatic; and - (CH 2 -0-CH 2 ) X CH 2 - wherein x is an integer from 1 to 6;
- R 24 is selected from the group: linear and branched, non-cyclic and cyclic, substituted and unsubstituted Ci -8 alkyl, wherein the said alkyl group can be single substituted by a homocyclic 6-membered aromatic group; homocyclic 6-membered aromatic groups, wherein preferably one of R 17 and R 18 is not aromatic; -(CH 2 -0- CH 2 ) X CH 2 - wherein x is an integer from 1 to 6; and L is a linker which can form a covalent bond with a targeting agent;
- R U wherein R is a single bond; or wherein R is selected from the group: linear and branched, non-cyclic and cyclic, substituted and unsubstituted Ci -8 alkyl, wherein the said alkyl group can be single substituted by a homocyclic 6-membered aromatic group; homocyclic 6-membered aromatic groups; wherein preferably one of R 17 and R 18 is not aromatic; -(CH 2 -0-CH 2 ) x CH 2 - wherein x is an integer from 1 to 6; and U is a physiochemistry modifying group selected from the group consisting of: -(CH 2 ) m S(V ,-(CH 2 ) m C(0)0; -(CH 2 ) m P(0)0 2 2 - -(CH 2 ) m NR 2 -(CH 2 ) m NH 2 ; -(CH 2 ) m NHR 32 ;
- a 6 , A 7 , A 8 , A 9 , and A 10 , A 11 , A 12 , A 13 are
- indol system can comprise a total of 1 N atoms, and which azaindol system can comprise a total of 2 N atoms;
- R 3 , R 4 , R 5 , R 6 , R 7 , R 8 R 9 R 10 are independently H or selected from the group consisting of:
- R 25 is selected from the group: linear and branched, non-cyclic and cyclic, substituted and unsubstituted Ci -2 o alkyl, wherein the said alkyl group can be single or multiple substituted by a homocyclic or heterocyclic 5-, 6- or 7-membered aromatic group which can be substituted by a linear or branched C1-C6 alkyl group; homocyclic and heterocyclic 5-, 6- or 7-membered aromatic groups which can be substituted by a linear of branched C1-C6 alkyl group; -(CH 2 -0-CH 2 ) x CH 2 - wherein x is an integer from 1 to 50; and L is a linker which can form a covalent bond with a targeting agent; and
- R U and OR U wherein R is a single bond; or wherein R is selected from the group: linear and branched, non-cyclic and cyclic, substituted and unsubstituted Ci -2 o alkyl, wherein the said alkyl group can be single or multiple substituted by a homocyclic or heterocyclic 5-, 6- or 7-membered aromatic group which can be substituted by a linear or branched Oi-Ob alkyl group; homocyclic and heterocyclic 5-, 6- or 7-membered aromatic groups which can be substituted by a linear or branched Oi-Ob alkyl group; -(CH 2 -0- CH 2 ) X CH 2 - wherein x is an integer from 1 to 50; and U is a physiochemistry modifying group selected from the group consisting of: -(CH 2 ) m S0 3 ,-(CH 2 ) m C(0)0 , (CH 2 ) m P(0)0 2 2 - -(CH 2 -
- a 6 , A 7 , A 8 , A 9 , and A 10 , A 11 , A 12 , A 13 are C, N, or and form a 6-membered aromatic ring which together with the pyrrolin derived ring to which they are attached form an indol or an azaindol system, and to which indol or azaindol system a further 6-membered ring is annulated which is formed by at least two of the substituents R 3 , R 4 , R 5 , R 6 , or R 7 , R 8 R 9 R 10 , resulting in a trinuclear ring in which 1, 2 or 3 C atoms may be replaced by N or + N and which are substituted by R 11 , R 12 , R 13 , R 14 , and R 15 , R 16 , R 17 ; R 18 ;
- R 11 , R 12 , R 13 , R 14 , and R 15 , R 16 , R 17 , R 18 are independently H or selected from the group consisting of:
- R 26 is selected from the group: linear and branched, non-cyclic and cyclic, substituted and unsubstituted Ci -2 o alkyl, wherein the said alkyl group can be single or multiple substituted by a homocyclic or heterocyclic C 5 -, G,- or G-aryl group which can be substituted by a linear or branched C 1 -C 6 alkyl group; homocyclic and heterocyclic C 5 -, G,- or G-aromatic groups which can be substituted by a linear or branched C 1 -C 6 alkyl group; -(CH 2 -0-CH 2 ) x CH 2 - wherein x is an integer from 1 to 50; and L is a linker which can form a covalent bond with a targeting agent;
- R U and OR U wherein R is a single bond; or wherein R is selected from the group: linear and branched, non-cyclic and cyclic, substituted and unsubstituted Ci -2 o alkyl, wherein the said alkyl group can be single or multiple substituted by a homocyclic or heterocyclic 5-, 6- or 7-membered aromatic group which can be substituted by a linear or branched Ci-C 6 alkyl group; homocycbc and heterocyclic 5-, 6- or 7-membered aromatic groups which can be substituted by a linear of branched Ci-C 6 alkyl group; - (CH 2 -0-CH 2 ) X CH 2 - wherein x is an integer from 1 to 50; and U is a physiochemistry modifying group selected from the group consisting of: -(CH 2 ) m S0 3 ,-(CH 2 ) m C(0)0 , - (CH 2 ) m P(0)0 2 2 -(
- a 6 , A 7 , A 8 , A 9 , and A 10 , A 11 , A 12 , A 13 are C, N, + N and either
- indol system can comprise a total of 1 N atoms and which azaindol system can comprise a total of 2 N atoms;
- R 3 , R 4 , R 5 , R 6 , R 7 , R 8 R 9 R 10 are independently H or selected from the group consisting of:
- R 25 is selected from the group: linear, non-cyclic, substituted and unsubstituted Ci-i 2 alkyl, wherein the said alkyl group can be single or multiple substituted by a homocyclic 6-membered aromatic group which can be substituted by a linear or branched C 1 -C 4 alkyl group; homocyclic 6- membered aromatic groups which can be substituted by a linear or branched C 1 -C 4 alkyl group; -(CH 2 -0-CH 2 ) X CH 2 - wherein x is an integer from 1 to 20;
- R 25 is selected from the group: linear, non-cyclic, substituted and unsubstituted Ci-i 2 alkyl, wherein the said alkyl group can be single or multiple substituted by a homocyclic 6-membered aromatic group which can be substituted by a linear or branched C 1 -C 4 alkyl group; homocyclic 6-membered aromatic groups which can be substituted by a linear or branched C 1 -C 4 alkyl group; -(CH 2 -0- CH 2 ) X CH 2 - wherein x is an integer from 1 to 20; and L is a linker which can form a covalent bond with a targeting agent; and
- R U and OR U wherein R is a single bond; or wherein R is selected from the group: linear, non-cyclic, substituted and unsubstituted Ci-i 2 alkyl, wherein the said alkyl group can be single or multiple substituted by a homocyclic 6-membered aromatic group which can be substituted by a linear or branched C1-C4 alkyl group; homocycbc 6- membered aromatic groups which can be substituted by a linear or branched C1-C4 alkyl group,; -(CH2-0-CH 2 ) X CH 2 - wherein x is an integer from 1 to 20; and U is a physiochemistry modifying group selected from the group consisting of: -(CffyfySCfy ,-(CH 2 ) m C(0)0-(CH 2 ) m P(0)0 2 2 -(CH 2 ) m NR 2 -(CH 2 ) m NH 2 ; -(CH 2 ) m
- R 11 , R 12 , R 13 , R 14 , and R 15 , R 16 , R 17 are independently H or selected from the group consisting of:
- R 26 is selected from the group: linear, non-cyclic, substituted and unsubstituted Ci-i 2 alkyl, wherein the said alkyl group can be single or multiple substituted by a homocyclic 6-membered aromatic group which can be substituted by a linear or branched C 1 -C 4 alkyl group; homocyclic 6- membered aromatic groups which can be substituted by a linear or branched C 1 -C 4 alkyl group; -(CH 2 -0-CH 2 ) X CH 2 - wherein x is an integer from 1 to 20;
- R 26 L and OR 26 L wherein R 26 is selected from the group: linear, non-cyclic, substituted and unsubstituted C R2 alkyl, wherein the said alkyl group can be single or multiple substituted by a homocyclic 6-membered aromatic group which can be substituted by a linear or branched C 1 -C 4 alkyl group; homocyclic G, aromatic rings which can be substituted by a linear or branched C 1 -C 4 alkyl group; -(CH 2 -0-CH 2 ) x CH 2 - wherein x is an integer from 1 to 20; and L is a linker which can form a covalent bond with a targeting agent; and c) R 26 U and OR 26 U, wherein R 26 is a single bond; or wherein R 26 is selected from the group: linear, non-cyclic, substituted and unsubstituted Ci-i 2 alkyl, wherein the said alkyl group can be single or multiple substituted by a homocyc
- a 6 , A-. A 8 , A 9 , and A 10 , An, An, An are C, N, or + N, and either
- indol system can comprise a total of 1 N atoms and which azaindol system can comprise a total of 2 N atoms;
- R 3 , R 4 , R 5 , R 6 , R 7 , R 8 R 9 R 10 are independently H or selected from the group consisting of:
- R 25 is selected from the group: linear, non-cyclic, substituted and unsubstituted Ci -8 alkyl, wherein the said alkyl group can be single substituted by a homocycbc 6-membered aromatic group; homocycbc 6- membered aromatic groups; -(CH 2 -0-CH 2 ) x CH 2 - wherein x is an integer from 1 to 12; b) R 25 L and -OR 25 L , wherein R 25 is selected from the group: linear, non-cyclic, substituted and unsubstituted Ci -8 alkyl, wherein the said alkyl group can be single substituted by a homocycbc 6-membered aromatic group; homocycbc 6-membered aromatic groups; -(CH 2 -0-CH 2 ) x CH 2 - wherein x is an integer from 1 to 12; and L is a linker which can form
- R U and -OR U wherein R is a single bond; or wherein R is selected from the group: linear, non-cyclic, substituted and unsubstituted Ci -8 alkyl, wherein the said alkyl group can be single substituted by a homocycbc 6-membered aromatic group; homocycbc 6-membered aromatic group; -(CH 2 -0-CH 2 ) x CH 2 - wherein x is an integer from 1 to 12; and U is a physiochemistry modifying group selected from the group consisting of: -(CH 2 ) m S0 3 ⁇ -(CH 2 ) m C(0)Cr, -(CH 2 ) m P(0)0 2 2 - -(CH 2 ) m NR 2 -
- a 6 , A 7 , A S , A 9 , and A l0 , An, A l2 , A are and form a 6-membered aromatic ring which together with the pyrrolin derived ring to which they are attached form an indol or an azaindol system, and to which indol or azaindol system a further 6-membered ring is annulated which is formed by at least two of the substituents R 3 , R 4 , R 5 , R 6 , or R 7 , R 8 R 9 R 10 , resulting in a trinuclear ring in which 1 or 2 C atoms may be replaced by N, and which are substituted by R 11 , R 12 , R 13 , R 14 , and R 15 , R 16 , R 17 ;
- R 11 , R 12 , R 13 , R 14 , and R 15 , R 16 , R 17 are independently H or selected from the group consisting of:
- R 26 H and OR 26 H wherein R 26 is selected from the group: linear, non-cyclic, substituted and unsubstituted Ci -8 alkyl, wherein the said alkyl group can be single substituted by a homocyclic 6-membered aromatic group; homocyclic 6- membered aromatic groups; -(CH 2 -0-CH 2 ) x CH 2 - wherein x is an integer from 1 to 12; b) R 26 L and OR 26 L, wherein R 26 is selected from the group: linear, non-cyclic, substituted and unsubstituted Ci -8 alkyl, wherein the said alkyl group can be single substituted by a homocyclic 6-membered aromatic group; homocyclic 6-membered aromatic groups; -(CH 2 -0-CH 2 ) x CH 2 - wherein x is an integer from 1 to 12; and L is a linker which can form a covalent bond with a targeting agent; and
- R U and OR U, wherein R is a single bond; or wherein R is selected from the group: linear, non-cyclic, substituted and unsubstituted Ci -8 alkyl, wherein the said alkyl group can be single substituted by a homocyclic 6-membered aromatic group; homocyclic 6-membered aromatic groups; -(CH 2 -0-CH 2 ) x CH 2 - wherein x is an integer from 1 to 12; and U is a physiochemistry modifying group selected from the group consisting of: -(CH 2 ) m NR 2 -
- a 6 , A 7 , A 8 , A 9 , and A l0 , An, A l2 , An are C, N, or + N, and either:
- indol system can comprise a total of 1 N atoms and which azaindol system can comprise a total of 2 N atoms;
- R 3 , R 4 , R 5 , R 6 , R 7 , R 8 R 9 R 10 are independently H or selected from the group consisting of:
- R 25 is selected from the group: linear, non-cyclic, substituted and unsubstituted Ci -8 alkyl, wherein the said alkyl group can be single substituted by a homocyclic 6-membered aromatic group; homocyclic 6- membered aromatic groups; -(CH 2 -0-CH 2 ) x CH 2 - wherein x is an integer from 1 to 6; b) R 25 L and -OR 25 L, wherein R 25 is selected from the group: linear, non-cyclic, substituted and unsubstituted Ci -8 alkyl, wherein the said alkyl group can be single substituted by a homocyclic 6-membered aromatic group; homocyclic 6-membered aromatic groups; -(CH 2 -0-CH 2 ) x CH 2 - wherein x is an integer from 1 to 6; and L is a linker which can form a covalent bond with a targeting agent; and
- R U and -OR U wherein R is a single bond; or wherein R is selected from the group: linear, non-cyclic, substituted and unsubstituted Ci -8 alkyl, wherein the said alkyl group can be single substituted by a homocyclic 6-membered aromatic group; homocyclic 6-membered aromatic group; -(CH 2 -0-CH 2 ) x CH 2 - wherein x is an integer from 1 to 6; and U is a physiochemistry modifying group selected from the group consisting of: -(CH 2 ) m S0 3 ⁇ -(CH 2 ) m C(0)0-, -(CH 2 ) m P(0)0 2 2 - -(CH 2 ) m NR 2 -
- a 6 , A 7 , A S , A 9 , and A l0 , An, An, A are C, N, or + N and form a 6-membered aromatic ring which together with the pyrrolin derived ring to which they are attached form an indol or an azaindol system, and to which indol or azaindol system a further 6-membered ring is annulated which is formed by at least two of the substituents R 3 , R 4 , R 5 , R 6 , or R 7 , R 8 R 9 R 10 , resulting in a trinuclear ring in which 1 or 2 C atoms may be replaced by N, and which are substituted by R 11 , R 12 , R 13 , R 14 , and R 15 , R 16 , R 17 ;
- R 11 , R 12 , R 13 , R 14 , and R 15 , R 16 , R 17 are independently H or selected from the group consisting of:
- R 26 H and OR 26 H wherein R 26 is selected from the group: linear, non-cyclic, substituted and unsubstituted Ci -8 alkyl, wherein the said alkyl group can be single substituted by a homocyclic 6-membered aromatic group; homocyclic 6- membered aromatic groups; -(CH 2 -0-CH 2 ) x CH 2 - wherein x is an integer from 1 to 6; b) R 26 L and OR 26 L, wherein R 26 is selected from the group: linear, non-cyclic, substituted and unsubstituted Ci -8 alkyl, wherein the said alkyl group can be single substituted by a homocyclic 6-membered aromatic group; homocyclic 6-membered aromatic groups; -(CH 2 -0-CH 2 ) x CH 2 - wherein x is an integer from 1 to 6; and L is a linker which can form a covalent bond with a targeting agent; and
- R U and OR U, wherein R is a single bond; or wherein R is selected from the group: linear, non-cyclic, substituted and unsubstituted Ci -8 alkyl, wherein the said alkyl group can be single substituted by a homocyclic 6-membered aromatic group; homocyclic 6-membered aromatic groups; -(CH 2 -0-CH 2 ) x CH 2 - wherein x is an integer from 1 to 6; and U is a physiochemistry modifying group selected from the group consisting of: -(CH 2 ) m S0 3 ⁇ -(CH 2 ) m C(0)0-, -(CH 2 ) m P(0)0 2 2 - -(CH 2 ) m NR 2 -
- X and Y are selected from the group consisting of: CR 29 R 30 , where R 29 and R 30 are each independently selected from H, unsubstituted and substituted linear or branched, cyclic or non-cyclic Ci-C 6 alkyl.
- R 29 and R 30 are each independently selected from H, unsubstituted and substituted non-cyclic linear and branched Ci- C 4 alkyl.
- X and Y are CR R , where R and R are each independently selected from H, unsubstituted and substituted Ci-C 2 alkyl,
- E and E’ are independently selected from H, unsubstituted and substituted linear or branched, cyclic or non-cyclic Ci-C 6 alkyl.
- E and E’ are independently selected from H and unsubstituted and substituted linear or branched, cyclic or non-cyclic C1-C4 alkyl.
- E and E’ are independently selected from H and methyl and ethyl, preferably methyl.
- alkyleneoxy group -(CH 2 -0-CH 2 ) x CH 2 - which is cited in the context with R l R 2 , R 3 , R 4 , R5, R 6 , R 7 , Re, R9, Rio, Rll, R12, Rl3, Rl4, Rl5,Rl6, Rl7, Rl8, Rl9,R20, R2I, R22, R23, R23, R24, R25, R 2 6, has a length defined by x wherein x is an integer from 1 to 50, preferably from 1 to 20, more preferably from 1 to 12, still more preferably from 1 to 8, i.e. 1,2, 3,4, 5, 6, 7 or 8, or x may be an integer from 1 to 6.
- R 24 , R 25 , R 26 have the meanings as defined for the general, the preferred, the more preferred and the still more preferred embodiments for the formula A.
- any of the above residues can have any of the following preferred meanings: H; a linear, non- cyclic, substituted and unsubstituted Ci 6 alkyl (methyl, ethyl, propyl, butyl, pentyl or hexyl) wherein the said alkyl group can be single substituted by a homocyclic 6-membered aromatic group, preferably phenyl; and homocyclic 6-membered aromatic groups, preferably phenyl, wherein preferably one of R 19 and R 20 is not aromatic in case of -NR 21 R 22 ; -(CH 2 -0-CH 2 ) x CH 2 - wherein x is an integer from 1 to 8, i.e.
- R 19 and R 20 and the case wherein R 19 and R 20 , together with the N atom to which they are attached form a 5- or 6-membered heterocycle, this heterocycle can contain one further heteroatom selected from O and N, wherein the heterocycle can be substituted by a linear or branched, cyclic or non cyclic Ci-C 6 alkyl group, in particular 4-cyclohexylpiperazinyl
- Each of the above residues R 1 - R 26 can have the above meanings in combination with any of the general, preferred, more preferred, still more preferred and most preferred meanings of any of the other substituents, i.e.
- R 19 can have the above meaning, and any of the other substituents R 1 - R 18 and R 20 - R 26 can have the general, preferred, more preferred, still more preferred and most preferred meanings.
- R 19 in -OR 19 is not H, in particular if the compound according to formula A does not contain at least 1 linker and/or 1 physiochemistry modifying group as defined in the context of the present application.
- linkers L are selected from the group consisting of: -NH 2 , -OH, -SH, -C(0)0 , -C(0)Cl, -(C0)0(C0)R 27 , -C(0)NHNH 2 , -C(O), - C(0)OR , wherein R is selected from the group consisting of H, alkyl and aryl; wherein R is derived from substituted and unsubstituted N-hydroxysuccinimide, substituted and unsubstituted N-hydroxysulfosuccinimide, nitrophenol, fluorophenol each bound via -O-; azide N 3 , -NCO, - NCS, -CHO, -COCH 2 I, phosphoramidityl, phthalamidyl, maleimide, an alkyne group in particular -CoCR 31 wherein R 31 is H or a Ci-Cg alkyl group, sulfonate est
- L has the following meaning:
- L is selected from the group consisting of: -NH 2 , -OH, -SH, -C(0)0 , C(0)Cl, -(C0)0(C0)R 27 , -C(0)NHNH 2 , -C(0) -C(0)0R 28 , wherein R 27 is selected from the group consisting of H, alkyl and aryl; wherein R 28 is derived from substituted and unsubstituted N-hydroxysuccinimide, substituted and unsubstituted N-hydroxysulfosuccinimide, nitrophenol, fluorophenol each bound via -O-; azide N 3 , -NCO, -NCS, -CHO, -COCH 2 I, phosphoramidityl, phthalamidyl, maleimide, an alkyne group in particular -C ⁇ CR 31 wherein R 31 is H or a Ci-Cg alkyl group, preferably H or a C1-C4 alkyl group
- L has the following meaning:
- L is selected from the group consisting of: -NEE, -OH, -SH, -C(0)0 , -C(0)Cl, -C(0)0R 28 , wherein R 28 is derived from substituted and unsubstituted N-hydroxysuccinimide, substituted and unsubstituted N-hydroxysulfosuccinimide, nitrophenol, fluorophenol each bound via -0-; azide N 3 , -NCO, -NCS, -CHO, phosphoramidityl, phthalamidyl, maleimide, an alkyne group in particular -C ⁇ CR 31 wherein R 31 is H or a Ci-Cg alkyl group, preferably H or a C 1 -C 4 alkyl group, sulfonate esters, alkyl halides, acyl halides, pentynoic acid, propargylic acid, 6- aminobenzo
- thiazole-2-carbonitrile 6-hydroxy benzo
- a 1,2- aminothiol group in particular L-cysteine or D-cysteine
- the substituents Q, Z, E’, E, X, Y, R -R and R -R and A -A have the general, the preferred, the more preferred, the still more preferred or the most preferred embodiments as defined above.
- R 19 in -OR 19 is not H, in particular if the compound according to formula A does not contain at least 1 linker and/or 1 physiochemistry modifying group as defined in the context of the present application.
- L has the following meaning:
- L is selected from the group consisting of: -OH, -SH, -C(0)0 , -C(0)0R 28 , wherein R 28 is derived from substituted and unsubstituted N-hydroxysuccinimide, substituted and unsubstituted N-hydroxysulfosuccinimide, nitrophenol, fluorophenol each bound via -0-; azide N 3 , -NCS, - CHO, phosphoramidityl, phthalamidyl, maleimide, an alkyne group in particular -C ⁇ CR 31 wherein R 31 is H or a Ci-Cg alkyl group, preferably H or a C 1 -C 4 alkyl group, sulfonate esters, alkyl halides, acyl halides, 6-aminobenzo
- 6-hydroxybenzo[cf]thiazole- 2-carbonitrile, a 1 ,2-aminothiol group, L-cysteine, and the substituents Q, Z, E’, E, X, Y, R'-R 29 and R -R and A -A have the general, the preferred, the more preferred, the still more preferred or the most preferred embodiments as defined above.
- R 19 in -OR 19 is not H, in particular if the compound according to formula A does not contain at least 1 linker and/or 1 physiochemistry modifying group as defined in the context of the present application.
- a 6 -A 13 and L can have the general, the preferred, the more preferred or the still more preferred meaning, whereas any other of the substituents Q, Z, E’, E, X, Y, R'-R 33 .
- a 6 -A 13 and L as defined above can have any of the meanings as defined for the general, the preferred, the more preferred or the still more preferred embodiments. This includes the cases that R 19 in - OR 19 is not H, in particular if the compound according to formula A does not contain at least 1 linker and/or 1 physiochemistry modifying group as defined in the context of the present application.
- Q can have the still more preferred meaning, and any of the substituents Q, Z, E’, E, X, Y, R'-R 33 .
- a 6 -A 13 and L can have the general, the preferred, the more preferred, the still more preferred or the most preferred meaning.
- L can have the more preferred meaning, and any of the substituents Q, Z, E’, E, X, Y, R'-R 33 .
- a 6 - A 13 and L can have the general, the preferred, the more preferred, the still more preferred or the most preferred meaning.
- a 6 , A 7 , A 8 , A 9 , and A 10 , A 11 , A 12 , A 13 are such that they form together with the pyrrolin derived ring to which they are attached an aromatic system selected from
- X and Y are selected from the group consisting of: CR 29 R 30 , where R 29 and R 30 are each independently selected from H, unsubstituted and substituted linear or branched, cyclic or non-cyclic Ci-C 6 alkyl, and the substituents Q, Z, E’, E, X, Y, R'-R 33 and A 6 -A 13 and L have the general, the preferred, the more preferred or the still more preferred meanings as defined above.
- R 19 in -OR 19 is not H, in particular if the compound according to formula A does not contain at least 1 linker and/or 1 physiochemistry modifying group as defined in the context of the present application.
- X and Y are selected from the group consisting of: CR 29 R 30 , where R 29 and R 30 are each independently selected from H, unsubstituted and substituted non-cyclic linear and branched C1-C4 alkyl, and the substituents Q, Z, E’, E, X, Y, R x -R 33 and A 6 -A 13 and L have the general, the preferred, the more preferred or the still more preferred meanings as defined above.
- R 19 in -OR 19 is not H, in particular if the compound according to formula A does not contain at least 1 linker and/or 1 physiochemistry modifying group as defined in the context of the present application.
- X and Y are CR R , where R and R are each independently selected from H, unsubstituted and substituted non-cyclic linear and branched Ci- C4 alkyl, and the substituents Q, Z, E’, E, X, Y, R'-R 33 and A 6 -A 13 and L have the general, the preferred, the more preferred or the still more preferred meanings as defined above.
- R 19 in -OR 19 is not H, in particular if the compound according to formula A does not contain at least 1 linker and/or 1 physiochemistry modifying group as defined in the context of the present application.
- X and Y are CR R , where R and R are each independently selected from H and methyl and ethyl, preferably methyl, and the substituents Q, Z, E’, E, X, Y, R'-R 33 and A 6 -A 13 and L have the general, the preferred, the more preferred or the still more preferred meanings as defined above.
- R 19 in -OR 19 is not H, in particular if the compound according to formula A does not contain at least 1 linker and/or 1 physiochemistry modifying group as defined in the context of the present application.
- X and Y are CR R , where R and R are each methyl, and the substituents Q, Z, E’, E, X, Y, R'-R 33 and A 6 -A 13 and L have the general, the preferred the more preferred or the still more preferred meanings as defined above.
- R 19 in -OR 19 is not H, in particular if the compound according to formula A does not contain at least 1 linker and/or 1 physiochemistry modifying group as defined in the context of the present application.
- E and E’ are independently selected from H, unsubstituted and substituted linear or branched, cyclic or non-cycbc Ci-C 6 alkyl, and the substituents Q, Z, E’, E, X, Y, R'-R 33 and A 6 -A 13 and L have the general, the preferred the more preferred or the still more preferred meanings as defined above.
- R 19 in -OR 19 is not H, in particular if the compound according to formula A does not contain at least 1 linker and/or 1 physiochemistry modifying group as defined in the context of the present application.
- E and E’ are independently selected from H and linear and branched Ci-C 6 alkyl and the substituents Q, Z, E’, E, X, Y, R x -R 33 and A 6 -A 13 and L have the general, the preferred, the more preferred or the still more preferred meanings as defined above.
- R 19 in -OR 19 is not H, in particular if the compound according to formula A does not contain at least 1 linker and/or 1 physiochemistry modifying group as defined in the context of the present application.
- E and E’ are independently selected from H and methyl and ethyl. In the most preferred embodiment, E and E’ are both methyl, and the substituents Q, Z, E’, E, X, Y, R'-R 33 and A 6 -A 13 and L have the general, the preferred, the more preferred or the still more preferred meanings as defined above. This includes the cases that R 19 in -OR 19 is not H, in particular if the compound according to formula A does not contain at least 1 linker and/or 1 physiochemistry modifying group as defined in the context of the present application.
- Preferable points of attachment for the linkers are the nitrogen on (i) the heterocycles of the dyes according to formula A, through for example R 17 and/or R 18 , R 1 and/or R 2 ; (ii) through any of the A6-A19 atoms when at least one of them is N;
- the dyes and the targeting agents are linked through the N of the heterocycles, most preferably through R 17 and/or R 18 , R 1 and/or R 2 or R 3 and/or R 7 if A 6 and/or A l0 are nitrogen.
- the dyes of the application have 1, 2, 3 or 4 linkers, preferably 1, 2 or 3 linkers, more preferably 1 or 2 linkers, in particular 2 linkers.
- the linkers are attached to the basic structure of the dye via a spacer group, which is thus preferred. It is also preferred to attach the linkers in the following positions: position R 1 , R 2 , or R 1 and R 2 ; in position R , R , or R and R ; or, if the ring annulated to the pyrrol structure contains a N atom, to this N atom, e.g., in positions R 3 , R 4 , R 7 and/or R 6 , preferably R 3 and/or R 7 .
- optical properties modulating group will in general be incorporated in the substituent Q.
- the physiochemical properties modulating group can be attached to any position in the dye basic structure, in principle. However, the positions laid out above will often be occupied by linkers or the optical properties modulating group. As a consequence, the physiochemical properties modulating group will often be attached in position R 3 , R 4 , R 5 , FT,. R 7 , R 8 , R 9 , R l0 , Rn, R 12 , R 13 , R 14 , R 15 , Ri 6 , Rn, Ri 8 and/or Rn.
- the number of physiochemical properties modulators is preferably 1, 2 or 3, more preferably 1 or 2.
- a physiochemical properties modulator can be attached with or without a spacer group, often without a spacer group.
- Formula B and formula C each depict one embodiment of the variant denoted B in the definition of formula A.
- Q, Z, E, E’, X, Y, and A 6 - A 15 have the meanings as set forth for formula A, including the general, the preferred, the more preferred and the still more preferred preferred embodiments, including the cases that R 19 in -OR 19 is not H, in particular if the compound according to formula A does not contain at least 1 linker and/or 1 physiochemistry modifying group as defined in the context of the present application;
- R 1 - R 14 and R 1 - R 16 respectively, have the meanings as set forth for formula B, including the general, the preferred, the more preferred and the still more preferred embodiments, including the cases that R 19 in - OR 19 is not H, in particular if the compound according to formula A does not contain at least 1 linker and/or 1 physiochemistry modifying group as defined in the context of the present application, except that a further 6-membered ring which is formed by at least two of the substituents R
- R 1 - R 17 have the meanings as set forth for formula A, including the general, the preferred, the more preferred and the still more preferred embodiments, including the cases that R 19 in -OR 19 is not H, in particular if the compound according to formula A does not contain at least 1 linker and/or 1 physiochemistry modifying group as defined in the context of the present application;
- R 1 - R 17 have the meanings as set forth for formula A, including the general, the preferred, the more preferred and the still more preferred embodiments, including the cases that R 19 in -OR 19 is not H, in particular if the compound according to formula A does not contain at least 1 linker and/or 1 physiochemistry modifying group as defined in the context of the present application, except that a further 6- membered ring which is formed by at least two of the substituents R 3 , R 4 , R 5 , R 6 , or R 7 , R 8 R 9 R 10 , resulting in a trin
- the dyes according to the application are asymmetrical in the sense that they do not have a C2 symmetry.
- One example for a group of such asymmetric molecules is B.
- Asymmetry can also be caused by one or more substituents (linkers, optical properties modulating groups and physiochemistry properties modulating groups) which are present only on one side of the molecule (i.e. on one side of the axe/ defined by Q and Z).
- the application provides a bioconjugate imaging agent comprising a fluorescent dye of the application linked to at least one targeting agent, see for example formula D below.
- the targeting agent is, in general, attached to the dye via a linking group, i.e. a group that is formed in a reaction with a complementary reactive group on the targeting agent.
- the targeting agent may comprise an“anchor group” (having been attached to it prior to the reaction with the dye), which anchor group comprises functional groups capable of reacting with the linker functional group, or of more easily reacting with the linker functional group than the functional groups present on the targeting agent.
- anchor groups comprise amino acids and bifunctional polyethylene glycols.
- the subject matter of the present application provides a use of the fluorescent dyes of the application as pH sensors.
- the fluorescent dyes can be used as a contrast reagents for optical acoustic/optoacoustic and for "shortwave infrared II (SWIR-II)" range (wavelengths from 0.9 to 1.7 microns) that has only recently been made practical by the development of Indium Gallium Arsenide (InGaAs) detectors.
- SWIR-II shortwave infrared II
- the application provides a compound that can be used as both fluorescent probe (novel aza-cyanine dye) linked to targeted moiety such as fatty acid and a probe that can be detected with another imaging modality such as 19F-MRI.
- fluorescent probe novel aza-cyanine dye
- a probe that can be detected with another imaging modality such as 19F-MRI.
- the application provides an in vitro imaging method, the method comprising
- the application provides the bioconjugate imaging agent of the application for use in a method of in vivo imaging, the method comprising:
- the application provides the bioconjugate imaging agent of the application for use in a method of in vivo optical imaging, the method comprising:
- the term“effective amount” refers to the amount of a compound sufficient to effect beneficial or desired results. Unless stated otherwise, an effective amount can be administered in one or more administrations, applications or dosages and is not intended to be limited to a particular formulation or administration route.
- the term“treating” includes any effect, e.g., lessening, reducing, modulating, ameliorating or eliminating, that results in the improvement of the condition, disease, disorder, and the like, or ameliorating a symptom thereof.
- Animal typically refers to a non-human mammal, including, without limitation, farm animals such as cattle, sheep, pigs, goats and horses; domestic mammals such as dogs and cats; laboratory animals including rodents such as mice, rats and guinea pigs; birds, including domestic, wild and game birds such as chickens, turkeys and other gallinaceous birds, ducks, geese, and the like.
- farm animals such as cattle, sheep, pigs, goats and horses
- domestic mammals such as dogs and cats
- laboratory animals including rodents such as mice, rats and guinea pigs
- birds including domestic, wild and game birds such as chickens, turkeys and other gallinaceous birds, ducks, geese, and the like.
- the term does not denote a particular age. Thus, both adult and new bom individuals are intended to be covered.
- the term 'preclinical' usually is used to describe tests carried out on such laboratory animals predominantly on rodents.
- the terms“patient” and“subject” refer to organisms to be subjected to, or treated by, the methods of the subject matter of the present application.
- Such organisms preferably include, but are not limited to, mammals (e.g., murines, simians, equines, bovines, porcines, canines, felines, and the like), and most preferably includes humans.
- mammals e.g., murines, simians, equines, bovines, porcines, canines, felines, and the like
- the term 'clinical' is usually tests carried out on larger vertebrate mammals and predominantly on humans.
- Alkyne refers to straight chain or branched hydrocarbon groups having from 2 to 10 carbon atoms, e.g., from 2 to 4 carbon atoms; and having at least 1, e.g., from 1 to 2, sites of double or triple bond unsaturation. This term includes, by way of example, bi-vinyl, allyl, and but-3-en-l- yl. Included within this term are the cis and trans isomers or mixtures of these isomers.
- Haloalkyl or“alkyl halide” refers to a substituted alkyl group, wherein one or more hydrogen atoms on the alkyl group have been substituted with a halo group. Examples of such groups include, without limitation, fluoroalkyl groups, such as trifluoromethyl, difluoromethyl, trifluoroethyl and the like.
- “Acyl” refers to the groups H— C(O)— , alkyl-C(O)— , substituted alkyl-C(O)— ,
- Carboxyl “carboxy” or“carboxylate” refers to— C0 2 H or salts thereof derived from C0 2
- Heteroaryl refers to an aromatic group of from 2 to 15 carbon atoms, such as from 3 to 10 carbon atoms and 1 to 10 heteroatoms selected from the group consisting of oxygen, nitrogen (referred to as aza in the application) and sulfur within the ring.
- heteroaryl groups can have a single ring (such as, pyrrole, pyridyl, imidazolyl or furyl) or multiple condensed rings in a ring system (for example as in groups such as, indolizinyl, quinolinyl, benzofuran, benzimidazolyl or benzothienyl), wherein at least one ring within the ring system is aromatic and at least one ring within the ring system is aromatic, provided that the point of attachment is through an atom of an aromatic ring.
- a single ring such as, pyrrole, pyridyl, imidazolyl or furyl
- multiple condensed rings in a ring system for example as in groups such as, indolizinyl, quinolinyl, benzofuran, benzimidazolyl or benzothienyl
- Heterocycle “heterocyclic,”“heterocycloalkyl,” and“heterocyclyl” refer to a saturated or unsaturated group having a single ring or multiple condensed rings, including fused bridged and spiro ring systems, and having from 3 to 20 ring atoms, including 1 to 10 hetero atoms. These ring atoms are selected from the group consisting of nitrogen (referred to as aza in application), sulfur, or oxygen,
- amino acid as used herein is understood to mean an organic compound containing both a basic amino group and an acidic carboxyl group. Included within this term are natural amino acids (e.g., L-amino acids), modified and unusual amino acids (e.g., D-amino acids), as well as amino acids which are known to occur biologically in free or combined form but usually do not occur in proteins.
- natural amino acids e.g., L-amino acids
- modified and unusual amino acids e.g., D-amino acids
- Natural amino acids include, but are not limited to, alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, serine, threonine, tyrosine, tyrosine, tryptophan, proline, and valine.
- amino acids include, but not limited to, arginosuccinic acid, citrulline, cysteine sulfmic acid, 3,4-dihydroxyphenylalanine, homocysteine, homoserine, ornithine, carnitine, selenocysteine, selenomethionine, 3-monoiodotyrosine, 3,5-diiodotryosine, 3,5,5'- triiodothyronine, and 3,3', 5,5'-tetraiodothyronine.
- Modified or unusual amino acids which can be used to practice the subject matter of the application include, but are not limited to, those derived from post translational modifications like phosphorylation and glycation, such as phosphoserine, phosphothreonine, phosphotyrosine, and others such as hydroxyproline, gamma- carboxyglutamate; hippuric acid, indole acetic acid, statine, penicillamine, ornithine, citruline and selenocysteine, D-amino acids, hydroxylysine, dehydroalanine, pyrrolysine, 2- aminoisobutyric acid, gamma aminobutyric acid, 5 -hydroxy tryptophan, S-adenosyl methionine, S-adenosyl homocysteine, 4-hydroxyproline, an N-Cbz-protected amino acid, 2,4- diaminobutyric acid, homoarginine, norleucine, N-methyla
- Protected amino acids are also covered and representative protecting groups such as carbobenzyloxy, (CbZ) at the amino terminus and others can be found and are known to those skilled in the art (See for example, Greene, T. W.; Wuts, P. G. M Protecting Groups In Organic Synthesis, 3rd edition, John Wiley & Sons, Inc., New York (1999)
- peptide describes a sequence of 2 to 50 amino acids, preferably 3 to 20 amino acids or peptidyl residues.
- the sequence may be linear, branched, cyclic such as resulting from intramolecular disulfide bonds from cysteinyl residues.
- Peptide sequences specifically recited herein are written or drawn out with the amino terminus on the left and the carboxy terminus on the right.
- D and L amino acids are both covered as well as protective groups like acetyl, acetoxymethyl, carbobenzyloxy, tert butyloxy and post translational modifications like methylation of arginine and lysine, phosphorylation and glycation of serine, threonine and tyrosine "OH" groups are also covered.
- a“pseudopeptide” or“peptidomimetic” is a compound which mimics the structure of an amino acid residue or a peptide, for example, by using linkers other than via amide linkages (pseudopeptide bonds) and/or by using non-amino acid substituents and/or a modified amino acid residue.
- A“pseudopeptide residue” means that portion of a pseudopeptide or peptidomimetic that is present in a peptide.
- the term“pseudopeptide bonds” includes peptide bond isosteres which may be used in place of or as substitutes for the normal amide linkage.
- saccharide refers to a sugar or other carbohydrate that could be derived or can be the result from the reduction and/or oxidation of a simple sugar.
- the saccharide can be a C6- polyhydroxy compound, with 2-6 hydroxy groups per unit, which could by cyclic or acyclic. Saccharides include inositols and their phosphorylated derivatives, Saccharides include simple sugars, i.e. C6 units (monomeric sugars) and their derivatives, as well as polysaccharides with two or more monosaccharide residues.
- the saccharide can include protecting groups on the hydroxyl groups, as described above in the definition of amino acids.
- the hydroxyl groups of the saccharide can be replaced with one or more halo or amino groups. Additionally, one or more of the carbon atoms can be oxidized, e.g., to keto or carboxyl groups.
- the term gly cation and glycosylation refer to the addition of saccharide molecules to appropriate residues such as hydroxyl and amino groups in peptides and proteins.
- acids include, but are not limited to, hydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric, maleic, phosphoric, glycolic, lactic, salicylic, succinic, toluene-p-sulfonic, tartaric, acetic, citric, formic, benzoic, malonic, naphthalene-2-sulfonic, benzenesulfonic acid, and the like.
- bases include, but are not limited to, alkali metals (e.g., sodium) hydroxides, alkaline earth metals (e.g., magnesium), hydroxides, ammonia, and compounds of formula NW 4 + , wherein W is C alkyl, and the like.
- compositions and kits are described as having, including, or comprising specific components, or where processes and methods are described as having, including, or comprising specific steps, it is contemplated that, additionally, there are compositions and kits of the present application that consist essentially of, or consist of, the recited components, and that there are processes and methods according to the present application that consist essentially of, or consist of, the recited processing steps.
- Certain compounds described herein may exist in particular geometric or stereoisomeric forms.
- the present application contemplates all such compounds, including cis- and trans-isomers, R- and S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, the racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the application.
- Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this application.
- the cyanine dyes derived from polymethine linked heterocycles such as Indocyanine Green (ICG) imaging agents are suitable chemicals which are used to provide the contrast or signal in fluorescence and that is detectable by optical imaging techniques.
- ICG Indocyanine Green
- the use of NIR fluorescent cyanine dyes for in vivo imaging started with the dye indocyanine green (ICG) because of its ready availability with good purity plus it had desirable NIR optical properties. Importantly, this is the only known NIR fluorescent dye approved by the US Food and Drug Administration (FDA) for monitoring cardiac output, hepatic function, and retinal angiography in humans.
- FDA US Food and Drug Administration
- various studies have shown that ICG accumulates in tumors through enhanced permeability and retention effects and it has also successfully been used to image tumors and lymph nodes.
- ICG derivatives or analogues have been designed and synthesized for different purposes, such as improving aqueous solubility or adding reactive functions for further bio-conjugation.
- a hydrophilic glucamide-derivatized indocyanine exhibited increased hydrophilicity and showed improved tumor-to-normal tissue contrast relative to ICG.
- a new class of fluorophores that incorporate multiple nitrogens exemplified by PPCy dyes has been synthesized via the reaction of diketopyrrolpyrrole with heteroarylacetonitriles. Although classified as cyanine dyes they are structurally different from the cyanine dyes. However they exhibit features for optical imaging, such as high quantum yields (>0.50), low photobleaching, and long fluorescence lifetimes (2.5 to 3.8 ns).
- the application provides cyanine compounds that incorporate additional nitrogen atoms, also referred to as aza, in the heterocycles bridging the polymethine as well as the polymethine linkage for appending additional charges and linkers as modifications that are used to modulate photochemical, biological, solubility as well as amenable to other modes of interrogation such as optoaccoustic methods.
- additional nitrogen atoms also referred to as aza
- aza moiety nitrogen
- a ratiometric measurement of the spectroscopic behavior of dyes that are differentially sensitive to acidic or basic environments can be exploited to indicate pH values.
- ratiometric methods are accrued because several parameters such as path length, local probe concentration, photobleaching and leakage from the cells are not important. For these reasons, stable cyanine dyes are needed for use in labeling biomolecules as well as in vivo imaging for the diagnosis and prognosis of diseases such as cancer, infectious disease imaging and metabolic activity. Such compositions and methods would aid in the analysis of responses to various therapies. The present subject matter satisfies these and other needs.
- the application provides novel class of fluorescent dyes belonging to the cyanine family (aza cyanine dyes), their derivatives for bioconjugation and imaging agents derived there from.
- the fluorescent dyes serve as labels and comprise aza substitution in the heterocycles as well as the bridging polymethine linkage.
- the fluorescent dyes of the application generally comprise two to eight nitrogen atoms in the heterocycles as well as the polymethine linkage connecting the heterocycles.
- the nitrogen substitution instead of the CH moiety provides a heteroatom that improves aqueous solubility, enables easier appending of groups through alkylation of the said nitrogen, reduces the p stacking that lowers the quantum yield in the corresponding CH analogues.
- the nitrogen henceforth referred to as aza provide charge based derivatives that can be tuned to the biological specificity.
- Prior art with azabenzolium cyanines developed as nucleic acid intercalating agents has also shown a concomitant shift in wavelength to the red compared to their CH analogues (Scheme 1).
- Optical techniques that need designer molecular probes for detecting and tracking molecular processes or biomarkers of interest are facilitated by the availability of the aza moiety for appending different chemical modifiers.
- the development of new molecular probes has attracted the attention of researchers for many decades because of their diverse applications in chemistry, biology, and medicine.
- optical imaging of molecular processes in living organisms has stimulated interest in the development of numerous molecular probes for use in the near-infrared (NIR) region (700- 900 nm) and there are about 6100 and more in the MIC AD database.
- NIR near-infrared
- NIR molecular probes offer two major advantages over those that emit at visible wavelengths.
- Molecular probes that emit light in the NIR region are expected to be suitable for in vivo imaging and with the substitution of the CH moiety with N provides structurally similar dyes with different photophysical, photochemical and biocompatibility that are superior to the carbon analogues.
- Prior art derivatives are usually derived from benzindolelinium and naphthindolelinium derivatives with the bridging methine linkages usually all carbon (Scheme 1), the current application is from pyridoindolelinium and quinolinoindolinium derivatives that contain within the bridge a hetero atom preferably nitrogen (Scheme 2).
- a quatemized heterocycle per example pyridoindolelinium and quinolinoindolinium
- a solubilizing groups or linkers for example pyridoindolelinium and quinolinoindolinium
- the quatemized heterocylic species is then coupled with a bisimine (bridge), which is an electrophilic reagent, obtained from Vilsmeier-Haack-Amold formylation of a piperidone derivative.
- a substituent is then attached to the nitrogen atom in the central heterocycle (bridge), the resulting central heterocycle formed is then quatemized.
- the bisimine is reacted with a different quaternary heterocycle with the final result of a symmetric or asymmetric compound.
- a salt of the fluorescent dyes of the application can be formed by any suitable counter ion.
- the counter ion selected from the group comprising but are not limited to chloride, bromide, iodide, triflate, tosylate, formate, acetate, trifluoro acetate, benzoate, oxalate, cyanide, cyanate, thiocyanate, hydrogen carbonate, carbonate, arsenate, arsenite, phosphate, hydrogen phosphate, dihydrogen phosphate, nitrite, nitrate, sulfate, hydrogen sulfate, thiosulfate, sulphite, perchlorate, chlorate, bromate, iodate, chlorite, hypochlorite, hypobromite, chromate, dichromate, permanganate, hexafluorophophate, tetraphenylborate, tetrafluoroborate.
- the fluorescent dyes of the application absorb in the region of 530nm to 880nm and have fluorescence emission in the region of 540-900nm when excited in between 530- 880nm.
- Q is Cl
- the resulting“indocarbocyanine” dye typically exhibits an absorption maximum near 550 nm. Where two double bonds are present, the “indodicarbocyanines” typically absorb maximally near 650 nm. The“indotricarbocyanine” dyes, where three double bonds are present, typically absorbs maximally near 750 nm.
- the addition of an extra ring as in 6,6,5 or benzindolenium heterocycle adds about l5-20nm to the absorption of the base indolenium described previously.
- Azindocyanine green derivatives the preferred dye of the application have three double bonds and two benzindolenium heterocycles bridging the polymethine chain, typically absorption ranges from 750-850 nm depending on additional substituents referred to as chemical modifiers (CM), solvent polarity and pH.
- CM chemical modifiers
- the azacyanine dyes have a high solubility in PBS buffer pH 7.4. This is more than 20 mM greater than commercial dyes such as ICG, 1.2 mM (1 mg/mL) in water, but it is not readily soluble in saline.
- the fluorescent dye of the application is a compound of formula E:
- Q’ is Cl, Br, I, -OR 19 , -SR 19 , or -NR 19
- R 20 , R 19 and R 20 are independently H or phenyl, wherein the phenyl can be substituted by Ci -6 alkyl, Ci- 6 fluroalkyl, -(CH 2 )o- 3 S0 3 ⁇ -(CH 2 )o- 3 S0 3 - alkali metal, -(CH 2 )o -3 COOH, -(CH 2 )o -3 COO-alkali metal, -NCO, -NCS, -(CH 2 ) 0-3 NH 2 or - (CH 2 ) O-3 N + H 3 , or R 19 and R 20 together with the nitrogen to which they are attached form a 5- or 6-membered heterocycle optionally containing one further heteroatom selected from O and N, wherein the heterocycle can be substituted by a linear or branched, cyclic or non-cyclic Ci_ 6 alkyl group;
- Ri ” , R 2 , R 3 , and Rr are independently absent, H, Ci -6 alkyl, or -(CH 2 ) I-6 L’, wherein L’ is - COOH, -COO-Ci- 6 alkyl, -NH2, -OH, -SH, -COO , SO 3 , S03-alkali metal, -COO-succinimide, - COO-sulfosuccininide, -NCO, -NCS, -COO-nitrophenyl, or -COO-fluorophenyl;
- a 6’ and A 10’ are independently C, N, or N + ;
- R 5 , R 6’ , R 9’ , and Rio ⁇ are independently H, or R and Rr, together with the carbons to which they are attached form a benzene, or R 9’ and Rio ⁇ together with the carbons to which they are attached form a benzene, wherein the benzene can be substituted by -(CH 2 )o- 3 SO 3 , -(CH 2 ) 0-3 S0 3 -alkali metal, -(CH 2 ) 0-3 COOH, or -(CH 2 ) 0-3 COO-alkali metal;
- Z’ is NR 17 or + NR 17 R 18 , wherein R 17 and R 18 are independently Ci -6 alkyl, -(CH 2 )i -3 ethynyl, - (CH 2 )i -6 L’, wherein L’ is -COOH, -COO-C ⁇ alkyl, -NH 2 , -OH, -SH, -COO , S0 3 , S0 3 -alkali metal, -COO-succinimide, -COO-sulfosuccininide, -COO-nitrophenyl, or -COO-fluorophenyl.
- a probe for multimodality imaging has a structure of the following formula F :
- Ri is -OR 19 or -SR 19 , wherein R 19 is phenyl substituted by -NHCSNH-R’” or -NHCONH-R’”, wherein R’” is a phenyl or heterocyclic 5-, 6-, or 7-memebered aromatic substituted by - (CH 2 )IO-3O COOH and at least one group selected from F and Ci_ 6 fluoroalkyl.
- the fluorescent dyes of the application are selected from the group comprising
- Xi is selected from H, SO 3 R, or C0 2 R,
- Z is selected from CH 2 , N-C I-6 alkyl (such as NMe), N + (Ci -6 alkyl) 2 (such as N + Me 2 ), N-ML, N + Me-ML,
- ML is selected from (CH 2 ) I-6 COOR (such as (CH 2 ) 5 COOR) and (CH 2 )i -5 S0 3 R (such as (CH 2 ) 4 S0 3 R),
- R is H, metal cation, ammonium, substituted or unsubstituted N-succinimide.
- Examples for preferred dyes according to the application include the following compounds I- XIX, XXIII and XXV - XXVIII,
- a bioconjugate imaging agent comprising the fluorescent dyes of the application.
- a bioconjugate imaging agent comprises a fluorescent dye of the application linked to at least one targeting agent (optionally by an anchor group or various anchor groups, i.e. 2, 3, 4 or 5 anchor groups).
- linking group - in general via a linking group - is understood to mean a chemical bond between atoms. Chemical bonds are known to the skilled artisan. In the context of the present application, the chemical bond is preferably an ionic bond or a covalent bond, most preferably a covalent bond.
- properties of a bioconjugate imaging agent can be adjusted by modifying the charge and molecular weight of the fluorescent dye (fluorophore), targeting agents and, in some cases, the anchor group.
- properties of the bioconjugate imaging agent can be adjusted by the various substituents as defined above in the specification (physiochemistry properties modulators and optical properties modulators).
- a targeting agent is a moiety that specifically recognizes a target, typically an in-vivo or an in- vitro biological target, such as a receptor or another cellular recognition moiety.
- a targeting agent is selected from the group comprising peptides (e.g., RGD peptide, which specifically binds to anb 3 integrin), small molecules, aptamers including peptide aptamers and DNA and RNA aptamers, antibodies, carbohydrates, saccharides, and nucleic acids.
- peptides e.g., RGD peptide, which specifically binds to anb 3 integrin
- small molecules e.g., RGD peptide, which specifically binds to anb 3 integrin
- aptamers including peptide aptamers and DNA and RNA aptamers
- antibodies e.g., carbohydrates, saccharides, and nucleic acids.
- the targeting agents comprise fluorophores of the current application linked to moieties that recognize cell surface receptors or report on the environment of the cell such as pH.
- a targeting agent is a peptide that is an enzymatic substrate such that when conjugated to the fluorescent dye of the application provides substantially no fluorescence. Cleavage of the peptide by a particular enzyme dissociates the fluorescent dye causing an increase in fluorescence. The increase in fluorescence reports on the presence of the activating enzyme.
- targeting agents either all from the same grouping or combinations thereof are linked to the fluorescent dye either directly or through linking groups.
- Preferable points of attachment for the linking groups are the nitrogen on (i) the heterocycles of the dyes of the application, through for example R and/or R and/or R , R and/or R ; (ii) through any of the A6-A19 atoms when at least one of them is N.
- Preferred compounds are linked through the N of the heterocycles (most preferably through R and/or R or R , R and/or R ), or if the ring annulated to the pyrrol structure contains a N atom, to this N atom, e.g., in positions R 3 , R 4 , R 7 and/or R 6 , preferably R 3 and/or R 7 .
- An anchor group is any functional group that can be used to link at least one targeting agent to the fluorescent dye of the application, in general via a linker.
- the anchor group will be attached to the targeting group, prior to linking it to the dye of the application.
- Useful anchor groups include both natural and non-natural amino acids, oligopeptides, for example linear or cyclic oligopeptides, nucleic acids, peptides or peptides moieties, such as glycine, b-alanine, g-aminobutyric acid or aminocaproic acid, as well as synthetic linker molecules such as aminoethyl maleimide or aminomethyl benzoic acid.
- the anchor group is a polymer such as homobifunctional or heterobifunctional polyethylene glycol (PEG).
- PEG polyethylene glycol
- the peptide optionally may include proteolytic cleavage site that can be cleaved with a variety of agents, for example, an enzyme. It is understood that there is no particular structural, size or content limitation for a given linker.
- Anchor groups can include, for example, a variety of functional groups such as maleimide, dithiopyridyl, thiol, azide, alkene, or alkyne that permit the assembly of molecules of diverse architecture.
- Anchor groups can be homofunctional linkers or heterofunctional linkers.
- amine (NH 2 )-functionalized moieties can be reacted with bifunctional cross-linkers designed to react with amino groups.
- Particularly useful conjugation reagents that can facilitate covalent linkage between, for example, a fluorescent dye (a fluorophore), and an enzymatically cleavable oligopeptide can include a N-hydroxysuccinimide (NHS) ester and/or a maleimide.
- the NHS ester can react with the amine group of, for example, a peptide or fluorophore.
- the maleimide can react with the sulfhydryl group of another molecule.
- anchor groups are bifunctional crosslinkers such as N- succinimidyl 3-(2-pyridyldithio)propionate (SPDP), long chain-SPDP, maleimidobenzoic acid- N-hydroxysuccinimide ester (MBS), succinimidyl trans-4-(maleimidylmethyl)cyclohexane-l- carboxylate (SMCC), succinimidyl iodoacetate (SIA).
- SPDP N- succinimidyl 3-(2-pyridyldithio)propionate
- MVS maleimidobenzoic acid- N-hydroxysuccinimide ester
- SCC succinimidyl trans-4-(maleimidylmethyl)cyclohexane-l- carboxylate
- SIA succinimidyl iodoacetate
- an anchor group can be branched, for example glutamic acid or 5- (aminomethyl) isophthalic acid, or a dendrimer, such as a lysine or glutamic acid dendrimer, with multiple M groups linked to a single site on the fluorescent dye (fluorophore).
- a dendrimer such as a lysine or glutamic acid dendrimer
- the biological modifier or physiochemistry modifier may be a PEG moiety that has a molecular weight, for example, from about 0.1 kDa to about 50 kDa, about 5 kDa to about 35 kDa, or about 10 kDa to about 30 kDa.
- the PEG may be dPEG, functionalized at a discrete molecular weight, for example, of about 1100 daltons.
- the PEG is methoxyPEG(5000)-succinimidylpropionate (mPEG-SPA), methoxyPEG(50000)-succinimidylsuccinate (mPEG-SS).
- PEGS are commercially available from Nektar Therapeutics SunBiowest or LaysanBio or NOF.
- the PEG moiety can be conjugated to reactive amines on the fluorescent dyes via a carboxyl functionality.
- the PEG modifier or physiochemistry modifier can be conjugated to the fluorescent dyes by using a thiol reactive cross linker and then reacting with a thiol group on the PEG.
- the PEG may be branched, or Y-shaped, as available from Nektar Therapeutics Ca, JenKem USA, or Quanta Biodesign or comb-shaped, or synthesized by coupling two or more PEGs to a small molecule such as glutamic acid.
- the chemical modifier or physiochemistry modifier may be dendrimers of various generations to provide multiple attachment points, such as those derived from polyamido(amine) PAMAM and characterized generationally by the number of functional groups and multiplicative radiating chains.
- the dendrimers are available from Merck, Dendritech and Polymer factory (Sweden).
- the biological chemical modifier or physiochemistry modifier can be polyvinylpyrrolidone (PVP)-type polymers.
- the biological or chemical modifier or physiochemistry modifier can be a functionalized polyvinylpyrrolidone, for example, carboxy or amine functionalized on one (or both) ends of the polymer (as available from Polymersource) or within the polymer chain.
- the biological chemical modifier or physiochemistry modifier can include Poly N-(2-hydroxypropyl)methacrylamide (HPMA), or functionalized HPMA (amine, carboxy, etc.), Poly(N-isopropyl acrylamide) or functionalized poly(N- isopropylacrylamide).
- a further aspect of the present application is a bioconjugate imaging agent comprising a targeting agent as described above linked to a dye of the basic structure as depicted in formula A.
- the bioconjugate imaging agent has the formula D.
- R 3 -R 10 , A 6 -A 13 , X, Y, Q, Z, E and E’ have the general, preferred, more preferred, still more preferred and most preferred meanings as defined in connection with formula A,
- R 1 and R 2 independently of each other have the meaning of R 23 as defined in connection with R 23 L for formula A, in the general, preferred, more preferred, still more preferred and most preferred meanings as defined in connection with formula A; and wherein both of R 1 ’ and R 2 ’ are present; or only one of R 1 and R 2 is present as attached to T via LG, in which case the other substituent R 1 or R 2 is absent, H or has the meaning of R 1 or R 2 as defined in connection with formula A, in the general, preferred, more preferred, still more preferred and most preferred meanings as defined in connection with formula A.
- the bioconjugate imaging agent may also have the formula G which has the same formula as formula A except that Q is R 21 -LG-T, -0-R 21 -LG-T, -SR 21 -LG-T, or -NR 21 R 22 -LG-T, R 21 and R 22 has the same meaning of R 21 and R 22 as defined in connection with R 21 L, -OR 21 L, -SR 21 L, and -NR 21 R 22 L for formula A.
- LG in both formula D and G is a linking group formed in the reaction of a linker as defined in the general, preferred, preferred, more preferred, still more preferred and most preferred meanings for formula A, with a complementary group on the targeting agent as defined in the general, preferred, more preferred and still more preferred meanings as defined in connection with formula A;
- T in both formula D and G is a targeting agent independently selected from receptors, ligands, antibodies, in particular monoclonal and polyclonal antibodies and fragments of these antibodies, antigens, peptides, (e.g., RGD peptide, which specifically binds to a n b3 integrin), enzyme substrates, enzymes, (specific) proteins and protein fragments, biotin, avidin, streptavidin, anti-biotin, carbohydrates, saccharides, lectin, DNA and fragments therof, RNA and fragments therof, aDNA and fragments therof, aRNA and fragments therof, hormones, folate, aptamers including peptide aptamers and DNA and RNA aptamers, enzyme substrates, and small molecules such as a moiety comprising fatty acid (e.g., an amino substituted fatty acid) or a moiety comprising amino (e.g., an aniline substituted or unsubstituted).
- the targeting agent as shown in formula D is formed in the reaction of the respective linker as defined in the general, preferred, preferred, more preferred, still more preferred and most preferred meanings for formula A, with a complementary group on the targeting agent as defined in the general, preferred, more preferred and still more preferred meanings as defined in connection with formula A.
- a targeting agent is, in a preferred embodiment of the invention, a ligand that is able to specifically interact with cell specific molecules via coordinative bonds in such a manner that results in a site-specific complex forming with the cell specific molecule.
- a coordinative bond is an intermolecular force, such as ionic bonds, hydrogen bonds and Van der Waals forces.
- the targeting agent typically acts as an inhibitor or an activator after it coordinatively bonds to the cell specific molecule.
- Targeting agents that form those site-specific complexes with cell specific molecules are known to a person skilled in the art or may be available from recent articles. For example, these targeting agents are well described in“CourseSmart International E-Book for Principles of Biochemistry” (D. L. Nelson and M. M. Cox, Eds. Palgrave Macmillan, 13.02.2013) and “Illustrated Dictionary of Immunology. Third Edition” (J. M. Cruse and R. E. Lewis, Eds. CRC Press, 20.04.2009).
- the targeting agent T is independently selected from the group cited above.
- a small molecule is a low molecular weight ⁇ 900 daltons organic compound that may help regulate a biological process, with a size on the order of 1CT 9 m.
- a small molecule is a molecule that binds to a specific biological target—such as a specific protein or nucleic acid— and acts as an effector, altering the activity or function of the target.
- a receptor is a molecule, in general a protein, that receives chemical signals from a ligand binding to it.
- receptors are molecules which are embedded in the membrane of a cell and are known to the person skilled in the art. They can also be used without the transmembrane part.
- the term receptor here also includes other proteins which are drug-targets, in particular enzymes, transporters and ion-channels
- a ligand is a substance that forms a complex with a receptor, in general a protein, by binding to a site thereof by intermolecular forces, such as ionic bonds, hydrogen bonds and Van der Waals forces.
- the ligand can be a small molecule, ion, or protein, a substrate, an inhibitor, an activator, a neurotransmitter.
- an antigen is a molecule that binds to Ag-specific receptors including antigens and is any molecule or molecule fragment that can be recognized by highly variable antigen receptors. Antigens are usually peptides, polysaccharides or lipids.
- antibody refers to immunoglobulins which are a class of soluble proteins found in body fluids of humans and other vertebrates. They are also termed“antibodies” and play a key role in the processes of recognition, binding and adhesion of cells. Antibodies are oligomeric glycoproteins which have a paramount role in the immune system by the recognition and elimination of antigens, in general bacteriae and viruses.
- the polymeric chain of antibodies is constructed such that they comprise so-called heavy and light chains.
- the basic immunoglobulin unit consists of two identical heavy and two identical light chains connected by disulfide bridges. There are five types of heavy chains (a, g, d, e, m), which determine the immunoglobulin classes (IgA, IgG, IgD, IgE, IgM).
- the light chain group comprises two subtypes, l and K.
- IgGs are soluble antibodies, that can be found in blood and other body fluids. They are built by B-cell derived plasma cells as response to and to neutralize bacterial or other pathogens.
- the two carboxy terminal domains of the heavy chains are forming the Fc fragment (“constant fragment”), the amino terminal domains of the heavy and light chains are recognizing the antigen and are named Fab fragment (“antigen-binding fragment”).
- Fc fusion proteins are created through a combination of an antibody Fc fragment and a protein or protein domain that provides the specificity for a given drug target.
- Other Fc fusion proteins are combinations of the Fc fragment with any type of therapeutic proteins or protein domains.
- the Fc part is considered to add stability and deliverability to the protein drug.
- Therapeutic antibodies and Fc fusion proteins are used to treat various diseases, prominent examples include rheumatoid arthritis, psoriasis, multiple sclerosis and many forms of cancer. Therapeutic antibodies can be monoclonal or polyclonal antibodies.
- immunoglobulin (antibody) types IgA, IgG, IgD, IgE, IgM can be used.
- IgM is preferred, and this term comprises natural, monoclonal and polyclonal antibodies, Fc fusion proteins and therapeutic antibodies (polyclonal and monoclonal).
- the respective bioconjugate may contain two targeting groups attached to the dye skeleton via LG, R 1 and R 2 , or only one of R 1 and R 2 is present to attach T via LG, meaning that the bioconjugate targeting agent contains only one targeting group.
- the other substituent R 1 or R 2 is absent, is H or has the meaning of R 1 or R 2 as defined in connection with formula A, in the general, preferred, more preferred still more preferred and most preferred meanings as defined in connection with formula A; or one of R 1 and R 2 has the meaning of R 23 L as defined in connection with formula A, in the general, preferred, more preferred, still more preferred and most preferred meanings, which means that a linker L is connected to the dye skeleton via R ; or one of R and R has the meaning of R U as defined in connection with formula A, in the general, preferred, more preferred and still more preferred meanings, which means that a physiochemistry modifying group U is connected to the dye skeleton via R 23 .
- Targeting agents are ligands that bind to receptors that are overexpressed on cancer cells, in a preferred embodiment. However, receptors overexpressed on cancer cells are also expressed on non-malignant cells in lower numbers. Therefore, ligand should have the affinity and specificity for overexpressed cell surfaced receptor.
- targeting agents known biological targets include for example transferrin, monoclonal antibodies (MAbs), polyclonal antibodies, peptides, EGF (epidermal growth factor), folate and aptamers.
- the targeting agents T can be the same or different. If T are different, the linking groups LG will preferably be different from each other, but may also be the same.
- the biomolecule imaging agents according to the above formula can be symmetrical, or asymmetrical in the sense that they do not have a C2 symmetry.
- bioconjugate imaging agents of the application are compounds XX, XXI, XXII, and XXVIII as shown in Examples.
- Another example of image-rendering bioconjugates of the application is the following compound: where the IgG molecule is a monoclonal or polyclonal antibody.
- Examples are known in the art of groups reacting with each other under formation of a covalent bond used to link two molecules.
- the below reactions lend themselves for attaching the targeting group to the dye according to the application.
- alkyl halides alcohols/phenols Ethers
- alkyl sulfonates carboxylic acids
- aryl halides mines ryl amines
- esters carboxylic acids
- bioconjugate imaging agents examples include the following compound XX, XXI, XXII, and XXVIII.
- bioconjugate XXVIII the“dye” is XXVII.
- Another aspect of the subject matter of the application is the pH sensitivity of the fluorescent dyes of application when the nitrogen atom in the heterocycle is substituted and another N atom is available for protonation or deprotonation.
- the excitation and emission wavelengths are pH dependent, a feature that enables lysosomal tracking as the environment is acidic.
- the indole nitrogen is protonated and the dyes of the application shift to longer wavelengths upon deprotonation as the conjugation is extended.
- Such dyes are pH sensors as their absorbance and consequently fluorescence changes as a consequence of the pH of the environment.
- the fluorescent dyes of the application are pH sensors and are defined by their ability to change the fluorescence absorption and emission properties as a consequence of protonation of the non quatemized nitrogen in the system.
- the application provides a use of the fluorescent dyes of the application as pH sensors.
- the application also provides a method for measuring a pH of a solution, wherein the fluorescent dyes of the application are used.
- the bioconjugate imaging agent according to the application binds to a biological target.
- the bioconjugate imaging agent permits detection of the presence of the biological target, preferably by visualisation, and of the disease or the diseased tissue expressing or presenting the biological target.
- the resulting bioconjugate imaging agent can have a high binding affinity to a target, for example, due to an interaction between the biomolecule and the target, for example, via receptor-ligand interaction, an antibody-antigen interaction, peptide-peptide receptor interaction, enzyme substrate-enzyme interaction, protein-protein receptor interaction, biotin-avidin (or streptavidin or anti-biotin) interaction, carbohydrate-lectin (or carbohydrate receptor) interaction, DNA(RNA)-aDNA(aRNA) interaction, hormone-hormone receptor interaction.
- receptor-ligand interaction for example, due to an interaction between the biomolecule and the target, for example, via receptor-ligand interaction, an antibody-antigen interaction, peptide-peptide receptor interaction, enzyme substrate-enzyme interaction, protein-protein receptor interaction, biotin-avidin (or streptavidin or anti-biotin) interaction, carbohydrate-lectin (or carbohydrate receptor) interaction, DNA(RNA)-aDNA(aRNA) interaction, hormone-hormone receptor interaction.
- T is a targeting agent independently selected from receptors, ligands, monoclonal and polyclonal antibodies and fragments of these antibodies, antigens, peptides, enzyme substrates, enzymes, (specific) proteins and protein fragments, biotin, avidin, streptavidin, anti-biotin, carbohydrates, saccharides, lectin, DNA and fragments therof, RNA and fragments therof, aDNA (antisense DNA) and fragments therof, aRNA (antisense RNA) and fragments therof, hormones, folate, aptamers, and enzyme substrates.
- a targeting agent independently selected from receptors, ligands, monoclonal and polyclonal antibodies and fragments of these antibodies, antigens, peptides, enzyme substrates, enzymes, (specific) proteins and protein fragments, biotin, avidin, streptavidin, anti-biotin, carbohydrates, saccharides, lectin, DNA and fragments therof, RNA and fragments the
- the targeting agent binds to targets that are overexpressed on cancer cells.
- targets overexpressed on cancer cells are also expressed on non- malignant cells in lower numbers. Therefore, the targeting agent used according to the application has affinity and specificity for overexpressed cell surface targets.
- Non-limiting examples include folate, transferrin, monoclonal antibodies (MAbs), peptides, EGF (epidermal growth factor) and aptamers.
- the targeting agent can be a receptor, a ligand, an antibody, preferably a monoclonal antibody, an antigen, a peptide, an enzyme substrate, an enzyme, a protein, biotin, avidin, streptavidin, anti-biotin, a carbohydrate, a saccharide, lectin, a carbohydrate, DNA, RNA, aDNA, aRNA, a hormone.
- bioconjugate imaging agents of the invention do not demonstrate any binding to or uptake by live cells and selectively only binds to necrotic cells. This is shown by the examples.
- the fluorescent dyes and the bioconjugate imaging agents of the invention are modified such that they carry a chelating agent (hereinafter denoted as“CA”).
- CA chelating agent
- the chelating agent lends itself for various purposes, e.g. for binding to a metal, preferably a radioactive metal.
- the binding of the metal to the chelate in general occurs via coordinate bonds (chelate effect), in which 2 or more atoms in the chelating agent bind to a single atom, in general a metal atom, Coordinative bonds are generally formed in a reaction between the metal atom (ion) and a free electron pair on an atom in the chelating agent.
- Chelating agents are well known to the person skilled in the art. In the context of the present invention, the use of chelating agents which bind to metals, preferably radioactive metals and/or known radioactive isotopes of known metals, in particular radioactive metals or radioactive isotopes of metals which lend themselves as tumor imaging agent and/or as MRI contrast agent, is preferred.
- the present invention preferably makes use of in particular 1,4,7, lO-Tetraazacyclododecane- l,4,7,l0-tetraacetic acid (DOTA), l,4,7-Triazacyclononane-l,4,7-triacetic acid (NOTA), Triethylenetetramine (TETA), Ethylenediaminetetraacetic acid (EDTA), 1,4,7- triazacyclononane-l-glutaric acid-4, 7-diacetic acid (NODAGA), and
- DTP A Diethylenetriaminepentaacetic acid
- Chelating agents used in the present invention can be used to bind radioactive metals or radioactive isotopes metals, preferably as 68 Gallium (68Ga), 64 Copper (64Cu) for tumor imaging using PET or m Indium (l l lln), or any other metal, preferablyGd ' for gadolinium-based MRI contrast agent, making this conjugate useful for various types of imaging modalities such as PET, SPECT, and MRI.
- radioactive metals or radioactive isotopes metals preferably as 68 Gallium (68Ga), 64 Copper (64Cu) for tumor imaging using PET or m Indium (l l lln), or any other metal, preferablyGd ' for gadolinium-based MRI contrast agent, making this conjugate useful for various types of imaging modalities such as PET, SPECT, and MRI.
- Chelating agents can be attached to any appropriate position in the dye molecules of the invention, i.e. the chelating agent can be in the position of any of the substituents Q, E, E’ and R 1 - R 16 .“Being in the position of any” in the present context means that the chelating agent can replace the respective substituent, or it can be attached to the respective substituent.“Attached to” here means that chelating agent is attached to the chemical entity as defined relative to the respective substituent, in the preferred, the more preferred, the still more preferred or the most preferred embodiments as defined above.
- CA may be attached to the respective group in a reach on transforming the reactive entities into different functionalities.
- the chelating agent replaces the respective substituent in the respective position, then the chelating agent can be attached to the respective atom directly.
- CA is attached to the respective atom on the dye via an atom previously present in the chelating agent, or via an atom in a functional group which has previously been attached to the CA. This is shown in the examples.
- CA is attached to a chemical entity linking it to the respective atom in the respective site of the fluorescent dye.
- these chemical entities are those defined for Q, alternative b) in connection with Formula A, in the general, preferred, more preferred, still more preferred and most preferred meanings as defined throughout the present application.
- the said chemical entities can, before the chelating agent is attached, be connected to the chelating agent or to the fluoresecent dye, before linking the chelating agent to the dye.
- the entity comprising CA is, in the most general meaning, defined as: R 35 CA, -OR 35 CA, -SR 35 CA and -NR 35 R 36 CA wherein R 35 and R 36 d are independently selected from the group consisting of: H, linear and branched, non-cyclic and cyclic, substituted and unsubstituted Ci -2o alkyl, wherein the said alkyl group can be single or multiple substituted by a homocyclic or heterocyclic 5-, 6- or 7- membered aromatic group which can be substituted by a linear or branched Ci-C 6 alkyl group; homocyclic and heterocyclic 5-, 6- or 7-membered aromatic rings which can be substituted by a linear or branched Ci-C 6 alkyl group, wherein preferably one of R 35 and R 36 is not aromatic in case of -NR 35 R 36 ; -(
- the above groups having R 35 and R 36 may each be an optical properties modifying group.
- the preferred, more preferred, still more preferred and most preferred meanings for CA attached to a chemical entity are, accordingly, those defined for Q b) in each of the preferred, more preferred, still more preferred and most preferred embodiments, with R 21 and R 22 being replaced by R 35 and R 36 .
- the chelating agent can be in any position Q, E, E’ and R 1 - R 16 , as stated above.
- the chelating agent is in position Q, R 1 and/or R 2 .
- CA is in position Q.
- the number of chelating groups attached to the fluorescent dyes (and, therefore, also to the bioconjugate imaging agents) of the invention may vary from 1 to 4, preferably from 1 to 3, more preferably from 1 to 2. In one particular preferred embodiment, this number is 1. In another preferred embodiment, this number is 2.
- Table 1 below cites various preferred chelating agents and the respective radioactive metals/isotopes which are bound by the agent. The table below is not meant to be limiting
- the amine-functionalized Compound VIII can then be coupled to a variety of chelating agents such as l,4,7,lO-Tetraazacyclododecane-l,4,7,lO-tetraacetic acid (DOTA) that have been modified to contain a N-Hydroxysuccinimide functional group as shown in reaction diagram 2.
- DOTA N-Hydroxysuccinimide functional group
- This reaction is completed by using the functionalized Compound VIII and the bi lly droxysuccinimide ester form of DOTA, which is commercially available, in the presence of 4 equivalents of N,N-Diisopropylethylamine (DIPEA) at room temperature in a nitrogen atmosphere.
- DIPEA N,N-Diisopropylethylamine
- Reaction diagram 2 Conjugation of Compound VIII to DOTA Radiolabeling of the DOTA-Compound VIII conjugate is accomplished using a 0.25M ammonium acetate buffer with a pH of 7.0 at 37°C for Indium-l l l, which is added to the solution in 0.4N hydrochloric acid and stirred for 45 minutes. Other metal chelates behave in a similar fashion for chelation procedures. The reaction with Indium-l l l is shown in reaction diagram 3.
- reaction diagram 5 an alternative starting structure (carboxylic) for conjugation and chelation of compound VIII
- reaction diagram 6 an alternative structure of compound VIII with a functional group of isothiocyanat for a conjugation with a modified DOTA compound
- reaction diagram 6 In reaction diagram 7 is shown a further structure of compound VIII with the isothiocyanat group as the starting compound for conjugation with a modified DOTA compound.
- DOTA and other chelating agents
- radioactive isotopes such as 68 Gallium (68Ga), 64 Copper (64Cu) for tumor imaging using PET or U1 lndium (l l lln) or any other metal such as Gd 3+ for gadolinium-based MRI contrast agent, making this conjugate useful for various types of imaging modalities such as PET, SPECT, and MRI.
- Corresponding compounds are also efficient fluorescent reagents, the conjugates can be used for optoacoustic, near-infrared imaging (600-900 nm) and shortwave infrared (SWIR II) range of wavelengths from 0.9 to 1.7 microns (see more details below).
- the molecule could also be envisioned for radiotherapy applications for local tumor irradiation when chelated to radioisotopes such as Lutetium or Yttrium ( 177 Lu,
- the carboxylic acid moiety on this molecule can also be used to couple to any other targeting ligand such as folic acid, cyclic RGD peptides (for alpha-v beta-3 receptor targeting) or antibody of choice (ex. Trastuzumab or TEM-l) or any other types of antibodies such as probodies ("masked” antibodies), nano-bodies, etc.
- any other targeting ligand such as folic acid, cyclic RGD peptides (for alpha-v beta-3 receptor targeting) or antibody of choice (ex. Trastuzumab or TEM-l) or any other types of antibodies such as probodies (“masked” antibodies), nano-bodies, etc.
- reaction diagram 8 an aza-fatty acid probe which can be used for image-guided surgery as some tumors show preferential uptake of fatty acids by comparison to normal tissue:
- reaction diagram 9 a probe for multimodality imaging:
- Reaction diagram 9 The final compound in reaction diagram 9 can be both a fluorescent probe and an imaging probe via imaging modality such as 19F-MRI.
- kits for fluorescence labelling of a biological sample comprising a dye as described above or a salt thereof, preferably a solution of the dye or the salt, or a bioconjugate imaging agent according to any of claims 7-9, and optionally a suitable buffer.
- Another aspect of the application provides methods for in vitro and in vivo imaging using the fluorescent dyes of the application including the dyes functionalized with a chelating agent including the embodiment with chelated metals in bioconjugate imaging agents.
- Optical imaging includes all methods from direct visualization without use of any device and use of devices such as various scopes, catheters and optical imaging equipment, for example computer based hardware for tomographic presentations.
- the imaging agents are useful with optical imaging modalities.
- Measurement techniques are known to the person skilled in the art and include, for example, endoscopy fluorescence endoscopy and further techniques which are known to the person skilled in the art;
- An imaging system useful in the practice of the application typically includes three basic components: (1) an appropriate light source for inducing excitation of the imaging agent, (2) a system for separating or distinguishing emissions from light used for fluorophore (fluorescent dye) excitation, and (3) a detection system.
- Exemplary detection systems include an endoscope, catheter, tomographic system, hand-held imaging system, an intraoperative microscope or a fluorescent microscope.
- Another aspect of the application provides a method of in vivo imaging, the method comprising: (a) administering to a subject a bioconjugate imaging agent of the application comprising the fluorescent dye of the application; (b) allowing the agent to distribute within the subject;
- Another aspect of the application provides a method of in vivo optical imaging, the method comprising: (a) administering to a subject a bioconjugate imaging agent of the application comprising the fluorescent dye of the application; (b) allowing the agent to distribute within the subject; (c) exposing the subject to light of a wavelength absorbable by the fluorescent dye and (d) detecting a signal emitted by the agent.
- Another aspect of the application provides a method of in vivo imaging, wherein the signal emitted by the bioconjugate imaging agent is used to construct an image.
- the image is a tomographic image.
- the subject matter of the present application is a method of in vivo optical imaging, wherein steps (a)-(c) are repeated at predetermined time intervals thereby to permit evaluation of the emitted signals of the targeting agent in the subject over time.
- the subject matter of the present application is a method of in vivo optical imaging, wherein steps (a)-(d) are repeated at predetermined time intervals thereby to permit evaluation of the emitted signals of the bioconjugate imaging agents in the subject over time.
- the subject matter of the present application is a method of in vivo imaging, wherein the subject is an animal or a human. In certain embodiments, the subject matter of the present application is a method of in vivo imaging, wherein in step (a) two or more bioconjugate imaging agents whose signal properties are distinguishable from one another are administered to a subject, wherein at least one of the bioconjugate imaging agents has a targeting agent. In certain embodiments, the subject matter of the present application is a method of in vivo optical imaging, wherein the illuminating and detecting steps are performed using an endoscope, catheter, tomographic system, hand-held optical imaging system, or an intraoperative microscope.
- Another aspect of the application provides a method of in vivo imaging, wherein the presence, absence, or level of emitted signal is indicative of a disease state.
- the subject matter of the present application is a method of in vivo imaging, wherein the method is used to detect and/or monitor a disease.
- the disease is selected from the group consisting of bone disease, cancer, cardiovascular disease, a neurogenerative disease, environmental disease, dermatological disease, a bone disease, trauma (e.g., injury), cell death, an autoimmune disease, immunologic disease, inherited disease, infectious disease, inflammatory disease, metabolic disease, and ophthalmic disease.
- any cell type, tissue or organ can be monitored including for example, liver, kidney, pancreas, heart, blood, urine, plasma, eyes, CNS (brain), PNS, skin, solid tumours, etc
- the terms“fluorescent dyes of the application” and“bioconjugate imaging agents” include dyes and bioconjugate imaging systems functionalized with a chelating agent including the embodiment in which metalas are chelated by chemically attached chelating agent. The above also applies with respect to any of the following embodiments.
- the above method of the application can be uses to detect the degree of cell death.
- the cell death results from a mechanism selected from apoptosis, necrosis, and necroptosis.
- the subject is a human or an animal.
- the animal is preferably a mammal.
- a compound, a dye according to the application is coupled to one or more of:
- Another aspect of the application provides a method of in vivo imaging, wherein, in step (a), cells labelled by a bioconjugate imaging agent are administered to the subject.
- the signal emitted by the agent is used to monitor trafficking and localization of the cells.
- such a method typically comprises (a) administering to a subject one or more of the bioconjugate imaging agents described herein, (b) allowing sufficient time to permit the agent to distribute with the subject, and (c) detecting a signal emitted by the bioconjugate imaging agents.
- the signal emitted by the agent can be used to construct an image, for example, a tomographic image.
- the foregoing steps can be repeated at predetermined time intervals thereby to permit evaluation of the emitted signals of the targeting agents in the subject over time.
- the subject may be a vertebrate, for example, a mammal, for example, a human.
- the subject may also be a non-vertebrate.
- Information provided by such in vivo imaging approaches can be used to detect and/or monitor a disease in the subject.
- exemplary diseases include, without limitation, autoimmune disease, bone disease, cancer, cardiovascular disease, environmental disease, dermatological disease, immunologic disease, inherited disease, infectious disease, metabolic disease, neurodegenerative disease, and ophthalmic disease.
- in vivo imaging can be used to assess the effect of a compound or therapy by using the bioconjugate imaging agents, wherein the subject is imaged prior to and after treatment with the compound or therapy, and the corresponding signal/images are compared.
- the dyes and the conjugates with the targeting agent and the conjugates with the target molecules may be used in optoacoustic imaging application.
- the dyes of the application may also be used as quenchers.
- the methods and compositions (fluorescent dyes and/or bioconjugate imaging agents) of the application can also be used in the detection, characterization and/or determination of the localization of a disease, including early disease, the severity of a disease or a disease-associated condition, the staging of a disease, and/or monitoring a disease.
- the presence, absence, or level of an emitted signal can be indicative of a disease state.
- examples of such disease or disease conditions that can be detected or monitored include inflammation (for example, inflammation caused by arthritis, for example, rheumatoid arthritis), cancer (for example, colorectal, ovarian, lung, breast, prostate, cervical, testicular, skin, brain, gastrointestinal, pancreatic, liver, kidney, bladder, stomach, leukemia, mouth, esophageal, bone), cardiovascular disease (for example, atherosclerosis and inflammatory conditions of blood vessels, ischemia, stroke, thrombosis, disseminated intravascular coagulation), dermatologic disease (for example, Kaposi's Sarcoma, psoriasis, allergic dermatitis), ophthalmic disease (for example, macular degeneration, diabetic retinopathy), infectious disease (for example, 1, viral, fungal and parasitic infections, including Acquired Immunodeficiency Syndrome, Malaria, Chagas Disease, Schistosomiasis), immunologic disease (for example
- the methods and compositions described herein can, therefore, be used, for example, to detect and/or quantify the presence and/or localization of elevated positively charged cell surfaces in a subject, including humans, for instance in infectious or apoptotic cells, and to detect and/or quantify the presence and/or localization of infection and cell death, including the presence of infectious or apoptotic areas within an organ.
- the methods and compositions described herein can also be used to detect and/or quantify apoptosis associated with diseases, disorders and conditions, including but not limited to preneoplastic/neoplastic disease including areas at risk for acute occlusion (i.e.
- the methods and compositions of the application can also be used in identification and evaluation of cell death, injury, apoptosis, necrosis, and hypoxia.
- the methods and compositions can also be used for drug delivery and to monitor drug delivery, especially when drugs or drug-like molecules are chemically attached to the fluorescent probes.
- Exemplary drug molecules include chemotherapeutic and cytostatic agents and photodynamic agents including but not limited to Photofrin, Lutrin, Antrin, aminolevulinic acid, hypericin, benzoporphyrin derivative, and porphyrins.
- the methods and compositions described herein can be used to image an infection in a subject.
- the method comprises administering to a subject (for example, a human or animal) an amount of one or more of the bioconjugate imaging agents described herein sufficient to facilitate in vivo and ex vivo imaging. After sufficient time to permit the agent to distribute within the animal or distribute within the area to be imaged, the presence and/or amount of the agent is determined. The presence and/or amount of the agent can then be used to create an image, for example, a tomographic image, representative of elevated positively charged cell surfaces within the tissues of the subject.
- compositions described herein can be used to image infections in a subject such as tuberculosis, Lyme disease, brucellosis, whooping cough, pneumonia, tetanus, diphtheria, typhoid fever, meningitis, cellulitis, impetigo, botulism, psittacosis, urethritis, enteritis, colitis, anthrax, Legionnaire's Disease, syphilis, tularemia, bronchitis, ulcers, boils, leptospirosis, listeriosis, gonorrhea, shigellosis, salmonellosis, cholera, cystitis, septicemia, txinoses, endocarditis,, toxic shock syndrome, scarlet fever, rheumatic fever,, and Rocky Mountain Spotted Fever.
- a subject such as tuberculosis, Lyme disease, brucellosis, whooping cough, pneumonia, tetan
- Another aspect of the application provides an in vitro imaging method, the method comprising: (a) contacting a sample with the bioconjugate imaging agent of the subject matter of the present application; (b) allowing the agent to bind to a biological target; (c) optionally removing unbound agent; and (d) detecting signal emitted from the agent thereby to determine whether the agent has been activated by or bound to the biological target.
- the sample is a biological sample.
- the imaging agents can be used in a variety of in vitro assays. After an imaging agent has been designed, synthesized, and optionally formulated, it can be tested in vitro by one skilled in the art to assess its biological and performance characteristics. For instance, different types of cells grown in culture can be used to assess the biological and performance characteristics of the agent. Cellular uptake, binding or cellular localization of the agent can be assessed using techniques known in the art, including, for example, fluorescent microscopy, FACS analysis, immunohistochemistry, immunoprecipitation, in situ hybridization and Forster resonance energy transfer (FRET) or fluorescence resonance energy transfer. By way of example, the agents can be contacted with a sample for a period of time and then washed to remove any free agents.
- FRET Forster resonance energy transfer
- the sample can then be viewed using an appropriate detection device such as a fluorescent microscope equipped with appropriate filters matched to the optical properties of a fluorescent agent. Fluorescence microscopy of cells in culture or scintillation counting is also a convenient means for determining whether uptake and binding has occurred. Tissues, tissue sections and other types of samples such as cytospin samples can also be used in a similar manner to assess the biological and performance characteristics of the agents. Other detection methods including, but not limited to flow cytometry, immunoassays, hybridization assays, and microarray analysis can also be used.
- bioconjugate imaging agents for example, agents containing the optical or radiolabel and drug molecule, can be used to ameliorate a symptom of, or treat, a particular disease or disorder.
- the method comprises (a) administering an amount of one or more the agents described herein sufficient to impart a therapeutic effect in the subject; and (b) permitting sufficient time for the agent to distribute within the subject or otherwise localize in a region of the subject to be treated and then, (c) depending on the therapeutic agent, optionally activating the agent to impart a therapeutic effect. For example, when the therapeutic agent is a radiolabel, no subsequent activation is required.
- the therapeutic agent is a photoreactive agent, for example, a dye used in photodynamic therapy
- exposing the agent to light having a wavelength that activates the agent may activate the agent.
- the agents can be used to treat a condition of interest, for example, a cancer, immune disorder, inflammatory disorder, vascular disorder and the like.
- the agents can be used to reduce tumor burden, to inhibit infection in an organ, or other region of interest in the subject, or reduce apoptotic cell proliferation within a subject.
- the molecular agents could be the fluorescent dyes of the application themselves in a particular environment such as solvent or vehicle in which it is administered or bioconjugates defined agents consisting of a fluorochrome (fluorescent dye) of the application conjugated through the linking group to a targeting agent as defined earlier.
- the molecular imaging agents are usually administered or delivered to a subject wherein the signal emitted by the agent is used to construct an image as described below.
- Bioconjugate imaging agents described herein may be formulated with one or more pharmaceutically acceptable carriers (additives) and/or diluents to provide a pharmaceutical composition.
- exemplary pharmaceutical compositions comprise one or more agents and one or more pharmaceutically acceptable carriers.
- the pharmaceutical compositions may be specially formulated for administration in solid or liquid form. Examples for administration include oral administration, parenteral administration, topical application, and transdermal administration.
- pharmaceutically-acceptable carriers include a liquid or solid filler, diluent, excipient, manufacturing aid (e.g., lubricant, talc magnesium, calcium or zinc stearate, or steric acid), or solvent encapsulating material, involved in carrying or transporting the subject compound from one organ, or portion of the body, to another organ, or portion of the body.
- manufacturing aid e.g., lubricant, talc magnesium, calcium or zinc stearate, or steric acid
- solvent encapsulating material involved in carrying or transporting the subject compound from one organ, or portion of the body, to another organ, or portion of the body.
- Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.
- Wetting agents, emulsifiers and lubricants, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants may also be present.
- Materials which can serve as pharmaceutically-acceptable carriers are known to the skilled artisan and include the typical materials.
- the application provides a pharmaceutically acceptable composition suitable for administration to a subject comprising a bioconjugate imaging agent and a pharmaceutically acceptable excipient.
- the fluorescent dyes of the application can be prepared as follows:
- bioconjugate imaging agents comprising fluorescent dyes of the application are derived according to the following scheme
- This application relates to new azacyanine dyes derived from pyridoindolelinium containing a heteroatom bridge preferably nitrogen. Incorporation of pyridoindolelinium into these cyanine dyes results in significantly increased solubility in both phosphate-buffered saline and water solutions over existing commercially available cyanine dyes ICG and IRDye800.
- the new azacyanine dyes XIII, XIV, XV, and II have cLogP values of -2.423, -3.545, -6.518, and -13.277 respectively, showing much greater hydophilicity than the commercially available ICG and IRDye800 dyes with cLogP values of 5.74 and -1.86.
- Probe XXI exhibits faster and more specific tumor uptake with the optimal background to noise ratio achieved in 2 hours post injection.
- IntegriSenseTM750 a successful commercially available small molecule integrin a n b3 antagonist NIR probe shows optimal background to noise ratio in 24 hours.
- RGD- ICG conjugate exhibited tumor uptake kinetics similar to probe XXI, but it also generated a lot of non-specific binding to various animal tissues, possible due to random precipitation of the hydrophobic ICG dye.
- Faster tumor binding kinetics of probe XXI was also observed in bigger animals like dogs where highest accumulation in the tumor tissue was detected within 6 hours post injection compared with 36 hours for IntegriSenseTM750 (See Figs. 11 and 12).
- Hydrazin derivatve (8) (1.0 g.), isopropyl methyl ketone (540 mg.), were placed at l30°C and stirred for 4h under nitrogen. Dilute the mixture with water and decant. Add NaOH 1M until ph 8 and formation of a brownish precipitate. Extract the solid with ethyl acetate 3 times. Yield 37%, HRMS calc: 211.1235; found 211.1236.
- Phosphorus oxychloride (0.1 ml) was added to cooled N,N-dimethylformamide (0.12 ml) at 0 °C. The temperature was maintained at 0 °C. Stirring was continued for another 30 minutes before the addition of 22 (0.12 g, 0.52 mmol). The mixture was then stirred at room temperature for 4 hours before it was poured into water (5 ml), concentrated and washed twice with ether affording a yellow oil (0.16 g, 88%). After dried under vacuum overnight the crude product was used directly in the next reaction without further purification.
- Dye XIII (3.0 mg, 0.0029 mmol) was dissolved in dry DMF (1 mL) under N 2 , and DIPEA (2.52 pL, 0.014 mmol) was added to the solution. The mixture was stirred at room temperature for 30 min. To the above solution under N 2 was then added TsTU (2.27 mg, 0.0074 mmol). The reaction mixture was stirred for 3 h and monitored by LC-MS to confirm formation of NH-ester. After 3 h, peptide c(RGDfK) (6.24 mg, 0.01 mmol) in DMF (0.4 mL) and DIPEA were added to the reaction mixture. The reaction was stirred for 18 h, while monitoring by LC-MS.
- Dye XIV (3.0 mg, 0.003 mmol) was dissolved in dry DMF (1 mL) under N 2 , and DIPEA (2.55 pL 3.5 equiv) was added to the solution. The mixture was stirred at room temperature for 30 min. To the above solution under N 2 was then added TsTU (3.1 mg, 0.01 mmol). The reaction mixture was stirred for 3h and monitored by LC-MS to confirm formation of NH-ester. After 4.5 h, peptide derivative c(RGDfK) (9 mg, 0.015 mmol) in DMF (1 mL) were added to the reaction mixture. The reaction was stirred for 24 h, while monitoring by LC-MS.
- the corresponding antibody was diluted with 2x volume of 0.1 M NaHCC (pH 8.5). 25 equivalents of fluorescent NHS dye XXVII (from 10 mM stock solution in DMSO) was added to the antibody solution and gently shacked in dark at room temperature for 2 hours. After incubation, antibody was purified by centrifuge filtration using desalting Zeba spin column 7K and stored in PBS at 4°C affording bioconjugate XXVIII. The number of fluorophores per antibody was determined by spectrophotometric analysis and determined to be approximately 2-3 fluorescent dyes per antibody.
- DOTA is attached in a chemical reaction to compound VIII shown again below.
- the reaction starts from Compound VIII shown below in Figure XXXX.
- Compound VIII can be functionalized with a group containing a benzene thiol, such as 4- aminobenzenthiol, or 2-(4-mercaptophenyl)acetic acid, shown in Figure 2.
- a benzene thiol such as 4- aminobenzenthiol, or 2-(4-mercaptophenyl)acetic acid
- the amine-functionalized Compound VIII is coupled to 1,4,7, lO-Tetraazacyclododecane- l,4,7,l0-tetraacetic acid (DOTA) modified to contain a N-Hydroxysuccinimide functional group as shown in reaction diagram 2..
- This reaction is completed by using the functionalized Compound VIII and the N-hydroxysuccinimide ester form of DOTA, which is commercially available, in the presence of 4 equivalents of N,N-Diisopropylethylamine (DIPEA) at room temperature in a nitrogen atmosphere.
- DIPEA N,N-Diisopropylethylamine
- Reaction diagram 2 Conjugation of Compound VIII to DOTA
- Radiolabeling of the DOTA-Compound VIII conjugate can be accomplished according to literature, 2 using a 0.25M ammonium acetate buffer with a pH of 7.0 at 37°C for Indium- 111, which is added to the solution in 0.4N hydrochloric acid and stirred for 45 minutes.
- Other metal chelates behave in a similar fashion for chelation procedures.
- the example of Indium- 111 chelation is shown reaction diagram 3
- this conjugate can be used for optoacoustic, near-infrared imaging (600-900 nm) and shortwave infrared (SWIR II) range of wavelengths from 0.9 to 1.7 microns (see more details below).
- This molecule could also be envisioned for radiotherapy applications for local tumor irradiation when chelated to radioisotopes such as Lutetium or Yttrium ( 177 Lu, 90 Y).
- Fig. la-b shows absorption and fluorescence spectra, and quantum yield QY of Compound
- Fig. 2a-b shows absorption and fluorescence spectra, and QY of Compound II.
- Fig. 3a-b shows absorption and fluorescence spectra, and QY of Compound III.
- Fig. 4a-b shows absorption and fluorescence spectra, and QY of Compound IV.
- Fig. 5a-b shows absorption and fluorescence spectra, and QY of Compound V.
- Fig. 6a-b shows absorption and fluorescence spectra, and QY of Compound VI.
- Fig. 7a-b shows absorption and fluorescence spectra, and QY of Compound VII.
- Fig. 8a-b shows absorption and fluorescence spectra, and QY of Compound VIII.
- Fig. 9a-b shows absorption and fluorescence spectra, and QY of Compound IX.
- mice Female nude mice 6-8 weeks of age were injected with 1M of 4T1 cells in lOOul of PBS subcutaneously into the right flank. Once the tumors reached approximately 0.5 cm J in size, animals were injected with 0.7 nmol of antibody conjugate XXVIII intravenously in 100 ul of PBS. Mice were then imaged at different time points using IVIS Spectrum instrument (Perkin Elmer) at recommended settings 745/810 nm excitation/ emission.
- IVIS Spectrum instrument Perkin Elmer
- mice bearing an established 4Tl-luc2 tumours implanted subcutaneously into the right flank were injected with the indicated imaging agent (a) Mice were imaged by IVIS Spectrum to show tumour localization and (b) NIR fluorescence images to show specific biomarker detection, after intravenously receiving 0.7 nmol of antibody conjugate XXVIII (Fig. 10).
- Fig. 11 shows NIR fluorescence images of 4Tl-luc2 tumour bearing mice at the indicated time points after intravenous injection of probe XXI, Integri SenseTM 750, and RGD-ICG.
- Fig. 12 shows the optimal background/noise ratio calculated from the region of interest of 4T1 tumour bearing mice (a) at 2h post injection of probe XXI and (b) 24h post injection of IntegriSenseTM750.
- Example 7 A kuvasz dog (male, 30 kg) diagnosed with mastocytoma tumor on his right leg was used for image guided surgery study. All canine studies were performed at Veterinair Verwijscentrum Gouda, Netherlands. Canine was injected intravenous catheterization into the cephalic vein with fluorescence probe XXI (180 nmol/kg) 6h prior to surgery. Canine underwent to general anesthesia prior to surgery. Image guided cancer surgery was performed using Solaris Open-air Fluorescence Imaging System (Perkin Elmer), equipped with four fluorescent channels (470 nm, 660 nm, 750 nm and 800 nm) to obtain real-time visualization of tumor imaging in ambient light Fig.
- Solaris Open-air Fluorescence Imaging System Perkin Elmer
- FIG. 13 shows (a) I.V. catheter injection in a 30 kg dog 6h before surgery with 180 nmol/kg of probe XXI, and (b) localization of mastocytoma tumour in dog's right leg.
- Fig. 14 shows (a) fluorescence image-guided surgical procedure of mastocytoma tumour resection.
- a mastocytoma tumour (solid arrow) is clearly identified by a rim around the tumor in vivo, 6h after injection of probe XXI. Normal tissue (dashed arrow) shows negligible background uptake of probe XXI.
- Fig. IS shows (a) no apparent fluorescence from residual tumour could be observed after the operation, and (b) after resection carried out under the guidance of fluorescent light and slicing of the same specimen, the rim around the tumor can be visualized ex vivo.
- Example 2 A labrador dog (male, 33 kg) diagnosed with mastocytoma tumor on his nose was used for image guided surgery study. All canine studies were performed at Veterinair Verwijscentrum Gouda, Netherlands. Canine was injected intravenous catheterization into the cephalic vein with fluorescence probe XXI (92 nmol/kg) 10 h prior to surgery. Canine underwent to general anesthesia prior to surgery. Image guided cancer surgery was performed using Solaris Open-air Fluorescence Imaging System (Perkin Elmer), equipped with four fluorescent channels (470 nm, 660 nm, 750 nm and 800 nm) to obtain real-time visualization of tumor imaging in ambient light Fig. 16 shows (a) I.V.
- Solaris Open-air Fluorescence Imaging System Perkin Elmer
- Fig. 17 shows (a) fluorescence image-guided surgical procedure of dog’s mastocytoma tumour and (b) after resection carried out under the guidance of fluorescent light and slicing of the same specimen, the rim around the tumor can be visualized ex vivo.
- Fig, 18 shows (a) cryogenic tissue damage with dye VI, the cells at the site of focal dry -ice treatment showed strong fluorescence signal whereas no signal was obtained from the viable cells, and (b) total photon flux of treated cells at different concentrations.
- Fig, 19 shows (a) cryogenic tissue damage with dye XIV, fluorescence of the dye XIV showed strong accumulation of fluorescence at the site of focal dry-ice treatment in the cryogenic tissue, (b) total photon flux of treated tissue at different concentrations
- Compound VIII has been shown to selectively target necrotic tissue in vivo. Cardiotoxin (10mM in 50pL of PBS) was injected into the right thigh of the mouse and 50pL of PBS was injected into the left thigh. 24 hours post-injection of toxin, Compound VIII (40pmoles in lOOpL PBS) was injected intravenously into the tail of the mouse. The results show that the dye selectively targets the necrotic area and clears through the kidneys instead of accumulating in the liver. The results are shown below in Figures 20 - 22. The brightnesses of the images are not on scale with one another. The quantification is shown on the same graph. Significant signal over-background ratios resulting from accumulation of the dye in necrosis areas observed as early as 10 min post-injection of the Compound VIII making it ideal for clinical translation.
- necrosis-targeting compound does not demonstrate any binding to or uptake by live cells and selectively only binds to necrotic cells. This should significantly minimize unwanted side effects when used in patients.
- the values for each well were consistent with that of the control group of wells that were not exposed to the dye in wells A1-A3.
- the bright well at F12 is a solution of Compound VIII at 5mM in PBS to insure imaging of the dye is occurring.
- the wells from B1-C10 are cells that were incubated with the dye; these wells were individually selected, and the radiance was compared to that of the control, with no significant difference between the groups.
- the image taken on the IVIS Spectrum is displayed below in Figure 7.
- Aza-dyes also have shown the potential to be used in the short wave infrared (SWIR) region located between l000-2000nm. This region is also known as near infrared II (NIR-II), although this region is usually defined as between l000-l700nm. It is important for in vivo imaging because tissue scattering and autofluorescence are significantly lower than in the NIR I (700-l000nm) region. This has led SWIR/NIR-II to be called a“tissue transparent” zone.
- SWIR/NIR-II near infrared II
- the camera used for obtaining the data has the following specs: "Princeton NIRvana detector, IsoPlane SCT320 spectrometer, Nikon inverted microscope, 658nm, 785nm and Xenon lamp/monochromator illumination sources"
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