New fluorescent compounds for tumor tissue labeling

Abstract

The present invention relates to a compound of formula (I): [Chemical Formula 1] (I) In the above formula, n1 and n2 are each integers from 0 to 15, R1, R2, R3, R4, R5 and R6 are each independently selected from H, OH, SH, NH2, SO3R10 and X-R11-Y, R10 and R'10 are independently H, Na or K, X, X' and X'' are independently O, S or NH, R11, R'11 and R''11 are selected from C1 to C15 alkyl, aryl, heteroaryl, (C1 to C15 alkyl)aryl, (C1 to C15 alkyl)heteroaryl, aryl (C1 to C15 alkyl), and heteroaryl (C1 to C15 alkyl); Y, Y' and Y'' are independently selected from H, halogen, COOR'10, or amide; R7 and R8 are each independently selected from H, OH, SH, NH2, C1 to C15 alkyl and X'-R'11-Y'; R9 is selected from H, OH, SH, NH2 and X''-R''11-Y'', and The above compound is a compound comprising at least one group X-R11-Y, X'-R'11-Y', or X''-R''11-Y'' where Y, Y' and / or Y'' is COOR'10. The present invention also relates to a method for preparing a compound of Formula I according to the present invention, as well as a method for labeling tumor tissue with one of the compounds prepared according to the present invention or according to the method of the present invention.

Description

Technology Field

[0001] The present invention relates to a novel fluorescent compound that can be used to label tumor tissue, a method for preparing the same, and its use as a means for monitoring, diagnosis, or assisting in cancer surgery.

[0002] Labeling tumor tissue with fluorescent compounds is attracting significant attention in the field of medical imaging, primarily because it allows for the localization of tumors. Background Technology

[0003] Fluorescent compounds have been used in medicine for over 50 years as markers for non-invasive imaging techniques for surveillance and / or diagnosis. The problem to be solved

[0004] The emergence of new fluorescence imaging technologies in surgical services requiring enhanced sensitivity and accuracy has led to research on new fluorescent molecules that provide better performance.

[0005] In relation to diseases such as cancer, it is necessary to possess not only a preferential distribution of fluorescent molecules in tumor tissue compared to healthy tissue but also sufficiently long fluorescence persistence to improve the specificity of the marker and provide assistance for surgical intervention, for example, by demarcating the area of ​​the tumor to be removed.

[0006] Existing specific fluorescent markers have limited fluorescence persistence, requiring surgery on the patient immediately after injection and making it impossible to obtain satisfactory demarcation of tumor tissue. In other cases, the marker does not accumulate sufficiently in the tissue, resulting in improper labeling and causing problems with detection. The localization of the lesion or tumor and, for example, its removal by surgery are incomplete.

[0007] Another problem with existing fluorescent markers, particularly indocyanine green (ICG), one of the few dyes used for tumor markers during surgery, is that the presence of neovascularization is required to obtain markers for tumor tissue. Furthermore, like other conventional dyes of the prior art, indocyanine green is visible only within tumor tissue for up to 24 hours after injection. This short duration results in poor visualization due to a low signal-to-noise ratio, as the dye circulating outside the tumor tissue is not effectively removed.

[0008] Another major disadvantage of existing compounds is that they cannot be used directly. In fact, for them to be used, they must be combined with other target molecules such as antibodies, proteins, molecules specific to tumor tissue, folic acid, or steroids.

[0009] The present invention enables the overcoming of the problems of the aforementioned prior art by providing fluorescent molecules that preferentially distribute to tumor tissue compared to healthy tissue and have sufficient persistence for use in imaging techniques for monitoring, diagnosis, and / or surgical assistance. These novel molecules have the major advantage of being able to be used alone and directly without prior binding due to their specific affinity for tumor tissue. Furthermore, compared to molecules of the prior art, they remain in tumor tissue for several days, which allows for more thorough removal of these fluorescent molecules circulating outside the tumor tissue, thereby improving visualization due to a better signal-to-noise ratio. means of solving the problem

[0010] The present invention first relates to a compound of formula (I):

[0011] [Chemical Formula 2]

[0012]

[0013] (I)

[0014] In the above formula,

[0015] n1 and n2 are integers from 0 to 15, respectively, and

[0016] R1, R2, R3, R4, R5, and R6 are each independently H, OH, SH, NH2, SO3R 10 and XR 11 Selected from -Y,

[0017] R 10 and R' 10 is independently H, Na, or K, and

[0018] X, X' and X'' are independently O, S or NH, and

[0019] R 11 , R' 11 and R'' 11 C1 to C 15 Alkyl, aryl, heteroaryl, (C1 to C 15 Alkyl)aryl, (C1 to C 15 Alkyl)heteroaryl, aryl (C1 to C 15 alkyl) and heteroaryl (C1 to C 15 Selected from alkyl;

[0020] Y, Y', and Y'' are independently H, halogen, COOR' 10 or selected from amides;

[0021] R7 and R8 are each independently H, OH, SH, NH2, C1 to C 15 Alkyl and X'-R' 11 Selected from -Y';

[0022] R9 is H, OH, SH, NH2 and X''-R'' 11 Selected from -Y'',

[0023] The above compound is Y, Y' and / or Y'' COOR' 10 at least one device XR 11 -Y, X'-R' 11 -Y' or X''-R'' 11Compound containing -Y''.

[0024] In the sense of the present invention, "C1 to C 15 "alkyl" is a cyclic, linear, or branched hydrocarbon chain comprising 1 to 15 carbon atoms, preferably 2 to 6 carbon atoms, more preferably 4 to 6 carbon atoms, particularly 5 carbon atoms, and this may be a methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2,2-dimethylbutyl, 2-methylpentyl, 2,2-dimethylpropyl, isopentyl, neopentyl, 2-pentyl, hexyl, 2-hexyl, 3-hexyl, 3-methylpentyl, peptic, octyl, nonyl, decyl, dodecyl, or palmityl chain.

[0025] In the sense of the present invention, "aryl" means an aromatic group comprising one or more optionally substituted aromatic rings.

[0026] In the sense of the present invention, "heteroaryl" means an aromatic group comprising one or more optionally substituted aromatic rings and one or more heteroatoms other than carbon and hydrogen.

[0027] In the context of the present invention, "aralkyl" means an aryl group substituted with one or more alkyl groups; said alkyl group preferably has 1 to 15 carbon atoms and is C1 to C 15 It can be an alkyl group.

[0028] In the context of the present invention, "heteroaralkyl" means a heteroaryl group substituted with one or more alkyl groups; said alkyl group preferably has 1 to 15 carbon atoms and is C1 to C 15 It can be an alkyl group.

[0029] According to a specific embodiment, in the above formula, n1 or n2 are independently 1, 2, 3, 4 or 5, more preferably 3 or 4.

[0030] According to another specific embodiment, in the above formula, n1=n2 and preferably 1, 2, 3, 4 or 5, more preferably 3 or 4.

[0031] According to another specific embodiment, the molecule is symmetric. In this case, COOR' carried by R9 10 A single group X''-R'' with Y'' 11 -Y'' and / or one is carried by one of R1, R2, R3 or R7, preferably by one of R1, R2 or R3, and the other is carried by one of R4, R5, R6 or R8, preferably by one of R4, R5 or R6, COOR' 10 Two groups XR with Y 11 Includes -Y.

[0032] According to a specific embodiment, R in the above chemical formula 10 and / or R' 10 can be the same. Similarly, X, X' and / or X'' can be the same, Y, Y' and / or Y'' can be the same, and R 11 , R' 11 and / or R'' 11 It can be the same.

[0033] The compound according to the present invention may be selected particularly from compounds of the following general formula:

[0034]

[0035] Here, X'' can be O, S, or NH and corresponds to the following expression:

[0036]

[0037]

[0038] .

[0039] The compound of Formula I according to the present invention may be selected particularly from the compound of Formula I in which R1, R2, R3, R4, R5, and R6 are not simultaneously H, in which case the compound according to Formula II below is excluded:

[0040] (II).

[0041] The compound of Formula I according to the present invention may preferably be selected from compounds of the following general formula:

[0042] [Chemical Formula 3]

[0043]

[0044] [Chemical Formula 4]

[0045]

[0046] Here, R1, R2, R3, R4, R 5, R 6, R 7, R8, and R9 is as defined above.

[0047] According to a specific embodiment, the compound according to the present invention may be selected from compounds of the following formula:

[0048] [Chemical Formula 5]

[0049] ,

[0050] [Chemical Formula 6]

[0051] ,

[0052] [Chemical Formula 7]

[0053]

[0054] Here, R1, R2, R3, R4, R 5, R 6, R 7, R8, and R9 is as defined above.

[0055] According to a preferred embodiment, the compound according to the present invention may be selected from the following compounds:

[0056] [Chemical Formula 8]

[0057]

[0058] [Chemical Formula 9]

[0059]

[0060] [Chemical Formula 10]

[0061]

[0062] [Chemical Formula 11]

[0063]

[0064] [Chemical Formula 12]

[0065]

[0066] [Chemical Formula 13]

[0067]

[0068] [Chemical Formula 14]

[0069]

[0070] [Chemical Formula 15]

[0071]

[0072] [Chemical Formula 16]

[0073] .

[0074] Secondly, the present invention relates to a method for preparing a compound of Formula I according to the present invention,

[0075] [Chemical Formula 17]

[0076]

[0077] and

[0078] [Chemical Formula 18]

[0079]

[0080] It includes the reaction step of.

[0081] It is preferable to carry out this reaction by reflux heating in the presence of sodium acetate in a mixture of acetic acid and acetic anhydride.

[0082] Thirdly, the present invention relates to a method for labeling tumor tissue with one of the compounds prepared according to the present invention or the method of the present invention.

[0083] In the context of the present invention, "tumor tissue" refers to tissue composed of tumor cells, which are abnormally proliferating cells, and supporting tissue also known as tumor stroma or stromal tissue, and consists of cells and extracellular material where tumor vascularization is located.

[0084] The fluorescent compounds according to the present invention have a special characteristic in that, after diffusing into the body, they become trapped in tumor tissue while being eliminated in healthy tissue. This special characteristic allows these fluorescent compounds to be used directly without pre-binding them to other label molecules, making them simpler, faster, and more effective than compounds of the prior art. It has been observed that this elimination in healthy tissue increases over time. Generally, these compounds are completely eliminated from healthy tissue 24 to 72 hours, preferably 36 to 60 hours, and more preferably 48 hours after administration. However, they remain trapped in tumor tissue. Since this characteristic provides distinct differentiation of tumor tissue compared to healthy tissue, these compounds can be used for monitoring, diagnosis, and / or surgical assistance in relation to cancerous diseases. This differentiation persists for 6 to 48 hours, preferably 12 to 36 hours, enabling targeted programming for diagnosis or surgery.

[0085] Accordingly, the compound according to the present invention can be used particularly in relation to cancer, such as hormone-dependent cancers like breast cancer or cancers of the digestive system like pancreatic cancer. In fact, in pancreatic cancer, it is particularly difficult to completely remove the tumor by surgery because the tumor is not easily distinguished. The use of the compound according to the present invention enables better visualization of the tumor contour due to the differentiation of markers between tumor tissue and healthy tissue, thereby enabling more effective tumor resection by surgery.

[0086] The present invention also relates to the use of one of the compounds according to the present invention or prepared according to the method of the present invention in a method for labeling tumor tissue.

[0087] These tissue labeling methods require the administration of a compound via an intravenous or intra-arterial route, or other blood vessels, particularly lymphatic vessels, or local injection or local application, preferably via an intravenous route.

[0088] The present invention also relates to a composition comprising one of the compounds prepared according to the present invention or according to the method of the present invention and at least one pharmaceutically acceptable adjuvant.

[0089] The present invention also relates to a method for labeling and / or detecting tumor tissue and / or for use in the surgical treatment of a tumor, comprising one of the compounds prepared according to the present invention or the method of the present invention, or one of the compounds prepared according to the present invention or the method of the present invention.

[0090] The present invention also relates to a method for detecting tumor tissue comprising the steps of labeling tumor tissue with one of the compounds prepared according to the present invention or the method of the present invention, and detecting by medical fluorescence imaging or fluorescence spectroscopy. Effects of the invention

[0091] The compound according to the present invention can be used particularly in relation to cancer, such as hormone-dependent cancers like breast cancer or cancers of the digestive system like pancreatic cancer. In fact, in pancreatic cancer, it is particularly difficult to completely remove the tumor by surgery because the tumor is not easily distinguished. The use of the compound according to the present invention enables better visualization of the tumor contour due to the differentiation of markers between tumor tissue and healthy tissue, thereby enabling more effective tumor resection by surgery. Brief explanation of the drawing

[0092] Figure 1 shows the median and standard deviation of the tumor / abdominal intensity ratio as a function of time after injection of compound 2 (CJ215) and ICG. Figure 2 shows the in vitro imaging results of a pancreatic tumor after injecting two compounds according to the present invention and a fluorescent agent (ICG) of the prior art. Specific details for implementing the invention

[0093] [Example]

[0094] Example 1:

[0095] [Chemical Formula 19]

[0096]

[0097] Compound ( 1 )

[0098] A mixture of 4-[(5-carboxypentyl)oxy]-6-sulfo-1-(4-sulfobutyl)-2,3,3-trimethyl-benz(e)indolium (internal and disodium salts) (9 g; 15 mmol), 2-chloro-1-formyl-3-(hydroxymethylene)-1-cyclohexene (1.30 g; 7.50 mmol), and sodium acetate (3 g; 36.6 mmol) was heated under reflux for 10 minutes in a 60 / 30 mixture of acetic acid and acetic anhydride. The reaction mixture was cooled to room temperature, the precipitate was separated by filtration, and washed with diethyl ether to obtain 4.33 g of green solid (yield: 43.9%). The unrefined product was purified by column flash chromatography (reverse-phase silica gel C18, acetonitrile 0-25% / water).

[0099] Example 2:

[0100] [Chemical Formula 20]

[0101]

[0102] Compound ( 2 )

[0103] Sodium methylate (440 mg; 7.6 mmol) was added to compound (1) (1 g; 0.76 mmol) in 500 mL of methanol solution. The reaction mixture was heated under reflux for 16 hours, concentrated under vacuum, and then filtered. The resulting residue was washed with cold methanol and acetone and vacuum dried to obtain 450 mg of green solid (yield: 45%). The unrefined product was purified by column flash chromatography (reverse-phase silica gel C18, acetonitrile 0-25% / water).

[0104] Example 3:

[0105] [Chemical Formula 21]

[0106]

[0107] Compound ( 3 )

[0108] MeSNa (106 mg; 1.5 mmol) was added to compound (1) (400 mg; 0.30 mmol) in a 20 mL solution of a 50 / 50 mixture of methanol / NMP (N-methyl-2-pyrrolidone). The reaction mixture was heated under reflux for 4 hours, and then diethyl ether (20 mL) was added to the mixture. The precipitate was filtered and washed with the same solvent to obtain 254 mg of crude product (yield: 61%; sulfur odor). The crude product was purified by column flash chromatography (reverse-phase silica gel C18, acetonitrile 0-25% / water).

[0109] Example 4:

[0110] [Chemical Formula 22]

[0111]

[0112] Compound ( 4 )

[0113] A mixture of 6-sulfo-1-(4-sulfobutyl)-2,3,3-trimethylbenz(e)indolium (internal salt and DCHA salt) (2 g; 4.7 mmol), 2-chloro-1-formyl-3-(hydroxymethylene)-1-cyclohexene (0.40 g; 2.35 mmol), and sodium acetate (0.9 g; 11 mmol) was heated under reflux for 15 minutes in a 50 / 20 mixture of acetic acid and acetic anhydride. The precipitate was separated by filtration, washed with ethanol and acetone, and vacuum dried to obtain 1.6 g of reddish-brown powder (yield: 63.8%). The unrefined product was purified by column flash chromatography (reverse-phase silica gel C18, acetonitrile 0-25% / water).

[0114] Example 5:

[0115] [Chemical Formula 23]

[0116]

[0117] Compound ( 5 )

[0118] 8 mL of 1 M methanolic KOH, 16 mL of DMSO, and compound (4) (500 mg; 0.25 mmol) were added to 3-(4-hydroxyphenyl)propionic acid (660 mg; 4 mmol). The reaction mixture was stirred at room temperature for 8 hours, and then 150 mL of ethyl acetate was added dropwise. The precipitate was separated by filtration, washed with ethanol and acetone, and vacuum dried to obtain 260 mg of green powder (yield: 45%). The unpurified product was purified by column flash chromatography (reverse-phase silica gel C18, acetonitrile 0-25% / water).

[0119] Example 6:

[0120] [Chemical Formula 24]

[0121]

[0122] Compound ( 6 )

[0123] 4-aminohydrocinnamic acid (816 mg; 4.9 mmol), 25 mL of DMSO, and triethylamine (500 mg; 4.9 mmol) were added to compound (4) (520 g; 0.49 mmol). The reaction mixture was stirred at room temperature for 8 hours, and then 200 mL of acetone was added dropwise. The precipitate was separated by filtration, washed with acetone, and vacuum dried to obtain 430 mg of red powder (yield: 74%). The unrefined product was purified by column flash chromatography (reverse-phase silica gel C18, acetonitrile 0-25% / water).

[0124] Example 7:

[0125] [Chemical Formula 25]

[0126]

[0127] Compound ( 7 )

[0128] 1 mL of 1 M methanolic KOH, 16 mL of DMSO, and compound (4) (500 mg; 0.25 mmol) were added to 4-mercaptohydrocinnamic acid (91 mg; 0.5 mmol). The reaction mixture was stirred at room temperature for 30 minutes, and then 50 mL of ethyl acetate was added dropwise. The precipitate was separated by filtration, washed with ethanol and acetone, and vacuum dried to obtain 310 mg of green powder (yield: 54%). The unpurified product was purified by column flash chromatography (reverse-phase silica gel C18, acetonitrile 0-25% / water).

[0129] Example 8: Comparison of the compound according to the present invention and a prior art fluorescent agent (ICG) for in vivo imaging of breast tumors

[0130] ICG (or indocyanine green / infracyanine) is a fluorescent agent of prior art that is already approved for use in humans for ophthalmic assessment of retinal diseases as well as for the evaluation of heart and liver function. It is also being evaluated in many clinical trials worldwide for mapping of ganglia from which tumors are expelled via near-infrared imaging or for surgical guidance during tumor expellation. ICG was compared with compound (2) according to the present invention, the synthesis of which is described in Example 2 above; this compound is referred to as CJ215 in this study.

[0131] This study included a total of 30 mice, divided into three groups. Tumor transplantation was performed by injecting 50,000 cells of 4T1-Dendra2 / 20 μl into two mammary glands in each mouse as a control.

[0132] Infusion of biomarkers (compound 2, referred to as CJ215 and ICG in this study) was performed after D9 tumor transplantation (to limit the appearance of necrosis in the tumor).

[0133] Changes in fluorescence signal intensity for each biomarker over time were evaluated from microscopic images. The ability of the two markers to generate signals specifically localized to the tumor was quantitatively assessed by calculating the ratio of the tumor-associated specific signal to the non-specific signal of the surrounding tissue.

[0134] The imaging protocol was performed for all mice at 2, 24, 48, 4, and 6 hours after injection. All images created at each acquisition time were acquired using the IVIS Spectral Imager (Perkin Elmer) with the following parameters:

[0135] Dendra2 GFP morphology detection (tumor detection):

[0136] - Excitation at 465 nm

[0137] - Emission between 520 and 580 nm

[0138] Biomarker Detection:

[0139] - Excitation at 745 nm

[0140] - Emission between 800 and 840 nm

[0141] Quantitative measurements were performed on the original, unconvolved images. For both phosphors, the acquisition time was parameterized in automatic mode. In this mode, the system determines the acquisition time required to reach a defined target value (6,000 counts) within an allowed time (fixed at 2 minutes).

[0142] Figure 1 shows the median and standard deviation of the tumor / abdominal intensity ratio as a function of time after injection of CJ215 and ICG.

[0143] The measurement of the tumor / abdominal strength ratio shown in this drawing may indicate the following:

[0144] - The intensity ratio is significantly higher for Compound 2 (CJ215) compared to ICG regardless of the time after injection (from 1.5x at 2 hours to over 3x at D+6), which translates to the ability to identify specific signals in tumors earlier and more specifically using Compound 2 (CJ215). These results also indicate the potential to significantly improve the specificity of signals to tumors by increasing the time between injection and imaging of Compound 2 (CJ215);

[0145] - The signal-to-noise ratio for Compound 2 (CJ215) continuously increases up to 6 days after injection, up to the last day of testing considered in this protocol. At this stage, ICG is no longer observed in the tumor (starting at 48h). The high stability of the intratumoral signal of Compound 2 (CJ215) compared to the surrounding tissue that removes the product improves tumor identification capabilities and contributes to significantly improving the fine differentiation of the tumor margin, which remains a problem for ICG.

[0146] Example 9: Comparison of two compounds according to the present invention and a prior art fluorescent agent (ICG) in in vitro imaging of a pancreatic tumor.

[0147] A model of orthotopic pancreatic adenocarcinoma was developed in mice. Tumor cells were amplified subcutaneously in SCID mice, and the resulting fragments were surgically transplanted into the pancreas of irradiated BALB / c nude mice.

[0148] Tumor development was monitored in vivo at three points D14, 28, and 36 by MRI (4.7T, PharmaScan, Bruker Biospin). Animals were exposed to weak fluorescence to minimize autofluorescence. Fluorescence imaging was performed using a charge-coupled device (CCD) camera (PhotonRT, BiospaceLab) with 700 nm excitation and 770 nm emission filters.

[0149] In vitro fluorescence images were acquired after in vivo imaging sessions performed at 2, 48, and 164 hours. Fluorescent compounds 2 (CJ215) and CJ319 (whose structures are described in detail below) according to the present invention were intravenously injected at a dose of 2 mg / kg on day 39 after tumor fragment transplantation, while the average tumor volume was approximately 70 mm³. Indocyanine green (ICG), a dye widely used for surgical imaging of tumors, was included as a control.

[0150] [Chemical Formula 26]

[0151]

[0152] (CJ319)

[0153] In vitro fluorescence imaging described in Fig. 2 indicated that two fluorescent compounds according to the present invention were present in the pancreas and tumor in nearly equal amounts 2 hours after injection. However, 48 hours after injection, a clear preferential distribution was observed in the tumor, and both compounds generated a fluorescent signal approximately four times higher in the tumor than in the surrounding pancreatic tissue. This effect persisted for 6 days after injection, but the signal decreased over time. In contrast, indocyanine green did not show any specific accumulation in the pancreas or tumor.

[0154] These results demonstrate the superiority of the compound of the present invention over the fluorescent agent of the prior art in terms of specific distribution level in tumor tissue.

Claims

Claim 1 Compound of Chemical Formula I: [Chemical Formula 27] (I) In the above equation, n1 and n2 are independently one of 1, 2, 3, 4, or 5, R3 and R6 are each H, and R1, R2, R4, and R5 are independently H, SO3R 10 and XR 11 Selected from -Y, wherein at least one of R1, R2, R4 and R5 is O-(CH2) 1-15 -COOR' 10 And, R1, R2, R3, R4, R5, and R6 are not all H at the same time, and R 10 is independently H, Na, or K, and R' 10 is Na, X and X'' are independently O or S, and R 11 and R'' 11 is independently C1 to C 15 Alkyl, aryl, heteroaryl, (C2 to C6 alkyl)aryl, (C2 to C6 alkyl)heteroaryl and aryl (C1 to C 15 Selected from alkyl; Y and Y'' are independently H, halogen, or COOR' 10 Selected from; R7 and R8 are C1 alkyl; and R9 is X''-R'' 11 -Selected from Y'', said compound is Y and / or Y'' is H or COOR' 10 at least one device XR 11 -Y or X''-R'' 11 Includes -Y''. Claim 2 In claim 1, a compound selected from compounds of the following chemical formula: [Chemical Formula 28] [Chemical Formula 29] In the above equation, R1, R2, R3, R4, R 5, R 6, R 7, R8, and R9 is as defined in Paragraph 1. Claim 3 In claim 1, a compound selected from compounds of the following chemical formula: [Chemical Formula 30] ,[Chemical Formula 31] ,[Chemical Formula 32] In the above equation, R1, R2, R3, R4, R 5, R 6, R 7, R8, and R9 is as defined in Paragraph 1. Claim 4 In claim 1, a compound selected from compounds of the following chemical formula: [Chemical Formula 33] [Chemical Formula 34] [Chemical Formula 35] [Chemical Formula 37] [Chemical Formula 38] [Chemical Formula 39] Claim 5 A method for manufacturing a compound according to any one of claims 1 to 4, [Chemical Formula 42] and [Chemical Formula 43] A manufacturing method comprising a reaction step. Claim 6 A composition comprising a compound according to any one of claims 1 to 4 for use in labeling or detecting tumor tissue or in the surgical treatment of a tumor. Claim 7 delete Claim 8 delete Claim 9 delete Claim 10 delete

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