Technical field
[2] Labeling of tumor tissue with fluorescent compounds is of considerable
interest in the field of medical imaging, because among other things it allows the
10 localization of tumors.
Prior art
[3] Fluorescent compounds have been used for more than fifty years in
medicine as markers in noninvasive imaging techniques for surveillance and/or
diagnosis.
15 Technical problem
[4] The emergence of new fluorescent imaging technologies in the service of
surgery, requiring improved sensitivity and accuracy, leads to research for new
fluorescent molecules giving better and better performance.
[5] In the context of diseases such as cancer, it is necessary in particular to
20 have a preferential distribution of the fluorescent molecules in the tumor tissues
relative to the healthy tissues, as well as sufficiently long persistence of the
fluorescence to allow improved specificity of labeling and to supply an aid for
surgical intervention, for example to delimit the regions of tumors to be removed.
[6] Certain existing fluorescent markers have limited persistence of
25 fluorescence, which necessitates operating on the patient soon after injection of
the marker and does not allow a satisfactory delimitation of the tumor tissue to be
obtained. In other cases, there is insufficient accumulation of the marker in the
tissues, which leads to poor labeling and therefore problems in detection. The
2
localization of lesions or of tumors and then their removal for example by surgery
is then incomplete.
[7] Another problem with the existing fluorescent markers, in particular
indocyanine green (ICG), which is one of the few dyes used for labeling tumors
5 during a surgical procedure, is the need for the presence of tumoral
neovascularization to obtain labeling of the tumor tissue. Moreover, indocyanine
green, like the other existing dyes in the prior art, is only visible in tumor tissues up
to 24h after its injection. This short duration does not give good elimination of the
circulating dye outside of the tumor tissues, which causes poor visualization as the
10 signal/noise ratio is low.
[8] Another major drawback of the existing compounds is that they cannot be
used directly. In fact, in order to be used they need to be coupled with other
targeting molecules such as antibodies, proteins, molecules specific to the tumor
tissue, folic acid, or steroids.
15 [9] The present invention allows us to overcome the problems of the prior art
explained above by supplying fluorescent molecules having preferential
distribution in the tumor tissues relative to the healthy tissues and sufficient
persistence for use thereof in imaging techniques for monitoring, diagnosis, and/or
as an aid in surgery. These new molecules have the major advantage that they
20 can be used alone and directly, without prior coupling, owing to their specific
affinity for tumor tissue. Moreover, relative to the molecules of the prior art, they
remain in the tumor tissues much longer, for up to several days, which allows
more thorough elimination of these fluorescent molecules circulating outside of the
tumor tissues, and thus improved visualization owing to a better signal/noise ratio.
25 Summary of the invention
[10] The present invention relates to a compound of formula (I)
[Chem. 1]
3
(I)
in which
n1 and n2 are each an integer from 0 to 15,
5 R1, R2, R3, R4, R5 and R6 are each selected independently from H, OH, SH, NH2,
SO3R10 and X-R11-Y,
R10, R'10 being independently H, Na or K,
X, X', X'' being independently O, S or NH,
R11, R'11, R''11 being selected independently from C1 to C15 alkyl, aryl, heteroaryl,
10 (C1 to C15 alkyl)aryl, (C1 to C15 alkyl)heteroaryl, aryl(C1 to C15 alkyl) and
heteroaryl(C1 to C15 alkyl);
Y, Y', Y'' being selected independently from H, halogen, COOR'10 or amide;
R7 and R8 each being selected from H, OH, SH, NH2, C1 to C15 alkyl, and X'-R'11-
Y';
15 R9 being selected from H, OH, SH, NH2 and X''-R''11-Y'',
said compound comprising at least one group X-R11-Y, X'-R'11-Y' or X''-R''11-Y''
with Y, Y', and/or Y'' which is COOR'10.
[11] The present invention also relates to the method of preparation of the
compounds of formula (I) according to the invention, as well as the method for
20 labeling tumor tissue with one of the compounds according to the invention or
prepared according to the method of the invention.
Disclosure of the invention
[12] The present invention relates firstly to a compound of formula (I)
[Chem. 2]
4
(I)
in which
n1 and n2 are each an integer from 0 to 15,
5 R1, R2, R3, R4, R5 and R6 are each selected independently from H, OH, SH, NH2,
SO3R10 and X-R11-Y,
R10, R'10 being independently H, Na or K,
X, X', X'' being independently O, S or NH,
R11, R'11, R''11 being selected independently from C1 to C15 alkyl, aryl, heteroaryl,
10 (C1 to C15 alkyl)aryl, (C1 to C15 alkyl)heteroaryl, aryl(C1 to C15 alkyl) and
heteroaryl(C1 to C15 alkyl);
Y, Y', Y'' being selected independently from H, halogen, COOR'10 or amide;
R7 and R8 each being selected from H, OH, SH, NH2, C1 to C15 alkyl, and X'-R'11-
Y';
15 R9 being selected from H, OH, SH, NH2 and X''-R''11-Y'',
said compound comprising at least one group X-R11-Y, X'-R'11-Y' or X''-R''11-Y''
with Y, Y', and/or Y'' which is COOR'10.
[13] In the sense of the present invention, "C1 to C15 alkyl" means a cyclic,
linear, or branched hydrocarbon chain containing from 1 to 15 carbon atoms,
20 preferably from 2 to 6 carbon atoms and even more preferably from 4 to 6 carbon
atoms, in particular 5 carbon atoms and that may in particular 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, heptyl, octyl, nonyl, decyl, dodecyl,
25 or palmityl chain.
[14] In the sense of the present invention, "aryl" means an aromatic group,
containing one or more aromatic rings, optionally substituted.
5
[15] In the sense of the present invention, "heteroaryl" means an aromatic
group, containing one or more aromatic rings, optionally substituted, and
comprising at least one heteroatom different than carbon and hydrogen.
[16] In the sense of the present invention, "aralkyl" means an aryl group
5 substituted with one or more alkyl groups; said alkyl groups may be C1 to C15 alkyl
groups, preferably containing from 1 to 15 carbon atoms.
[17] In the sense of the present invention, "heteroaralkyl" means a heteroaryl
group substituted with one or more alkyl groups; said alkyl groups may be C1 to
C15 alkyl groups, preferably containing from 1 to 15 carbon atoms.
10 [18] According to a particular embodiment, in the above formula, n1 or n2 are,
independently of one another, equal to 1, 2, 3, 4 or 5, even more preferably 3 or 4.
[19] According to another particular embodiment, in the above formula n1=n2
and is preferably equal to 1, 2, 3, 4 or 5, even more preferably 3 or 4.
[20] According to another particular embodiment, the molecule is symmetric. In
15 this case, it comprises a single group X''-R''11-Y'' with Y'' which is COOR'10 that is
carried by R9 and/or 2 groups X-R11-Y with Y which is COOR'10, one carried by
one of R1, R2, R3 or R7, preferably one of R1, R2 or R3 and the other carried by one
of R4, R5, R6 or R8, preferably one of R4, R5 or R6.
[21] According to a particular embodiment, in the above formula, R10, and/or
20 R'10, may be identical. Similarly, X, X', and/or X'' may be identical, Y, Y', and/or Y''
may be identical, R11, R'11, and/or R''11 may be identical.
[22] The compounds according to the invention may in particular be selected
from the compounds of the following general formula:
25 for which X'' may be O, S or NH, corresponding to the following formulas:
6
.
[23] The compounds of formula (I) according to the invention may in particular
5 be selected from the compounds of formula (I) for which R1, R2, R3, R4, R5 and R6
are not all simultaneously H, which excludes in this case the compounds
according to the following formula (II):
(II).
[24] The compound of formula (I) according to the invention may preferably be
10 selected from the compounds of the following general formulas:
7
[Chem. 3]
[Chem. 4]
5
in which R1, R2, R3, R4, R5, R6, R7, R8 and R9 are as defined above.
[25] According to a particular embodiment, the compounds according to the
invention may be selected from the compounds of the following formulas
[Chem. 5]
10 ,
[Chem. 6]
8
,
[Chem. 7]
5 in which R1, R2, R3, R4, R5, R6, R7, R8 and R9 are as defined above.
[26] According to a preferred embodiment, the compounds according to the
invention may be selected from the following compounds:
[Chem. 8]
10
[Chem. 9]
9
[Chem. 10]
5 [Chem. 11]
[Chem. 12]
10
[Chem. 13]
10
[Chem. 14]
5
[Chem. 15]
[Chem. 16]
10 .
11
[27] The present invention relates secondly to the method of preparation of the
compounds of formula (I) according to the invention comprising a reaction step
between:
[Chem. 17]
5
and
[Chem. 18]
[28] This reaction is preferably carried out by heating under reflux in the
10 presence of sodium acetate in a mixture of acetic acid and acetic anhydride.
[29] The invention relates thirdly to the method for labeling tumor tissue with
one of the compounds according to the invention or prepared according to the
method of the invention.
[30] In the sense of the present invention, "tumor tissue" means tissue
15 consisting of tumor cells, which are abnormal proliferating cells, and of a
supporting tissue, also called tumoral stroma or interstitial tissue, composed of
cells and extracellular substance in which the tumoral vascularization is located.
[31] The fluorescent compounds according to the invention have the particular
feature, after they have diffused in the body, of being trapped in tumor tissue,
20 whereas they are eliminated from healthy tissues. This particular feature makes it
possible to use these fluorescent compounds directly, without prior coupling to
another labeling molecule, thus making their use simpler, quicker and more
effective than that of the compounds of the prior art. It was observed that this
elimination from healthy tissues increases over time. In general, between 24 and
25 72 hours, preferably between 36 and 60 hours and more preferably 48 hours after
12
administration of these compounds, their elimination from healthy tissues is total.
However, they remain trapped in the tumor tissues. This property gives a clear
differentiation of tumor tissues relative to healthy tissues and thus these
compounds can be used in applications of monitoring, diagnosis and/or as an aid
5 to surgery in a context of cancerous diseases. This differentiation lasts for 6 to 48
hours, preferably 12 to 36 hours, allowing targeted programming of diagnosis or
surgery.
[32] The compounds according to the invention may thus be used in particular
in the context of cancers, for example hormone-dependent cancers, such as
10 breast cancer or digestive system cancers, such as pancreatic cancer. In fact, in
pancreatic cancer, the tumors are particularly difficult to remove completely by
surgery, as they are not easily delimited. The use of the compounds according to
the invention makes it possible to obtain better visualization of the contours of the
tumors owing to the differentiation of labeling between tumor tissue and healthy
15 tissue, and thus more effective tumor resection by surgery.
[33] The invention also relates to the use of one of the compounds according
to the invention or prepared according to the method of the invention in a method
for labeling tumor tissue.
[34] This method of labeling tissues requires administration of the compounds
20 by the intravenous or intraarterial route, or in another vessel, in particular a
lymphatic vessel, or by local injection, or by local application, preferably by the
intravenous route.
[35] The invention further relates to a composition comprising one of the
compounds according to the invention or prepared according to the method of the
25 invention and at least one pharmaceutically acceptable adjuvant.
[36] The invention also relates to one of the compounds according to the
invention or prepared according to the method of the invention or a composition
comprising one of the compounds according to the invention or prepared
according to the method of the invention for use thereof in a method of labeling
30 and/or detection of tumor tissue, and/or in the surgical treatment of tumors.
13
[37] The invention also relates to a method for detecting tumor tissue
comprising a step of labeling tumor tissue with one of the compounds according to
the invention or prepared according to the method of the invention, and a step of
detection by medical fluorescence imaging or fluorescence spectrometry.
5 Figures
Fig. 1
[38] [Fig. 1] shows the median values and standard deviations of the
tumor/abdomen intensity ratios as a function of time post-injection of compound 2
(CJ215) and of ICG.
10 Fig. 2
[39] [Fig. 2] shows the results of ex vivo imaging of pancreatic tumors after
injection of two compounds according to the invention and of a fluorescent agent
of the prior art (ICG).
Examples
15 [40] Example 1:
[Chem. 19]
SO3Na
N
O
(CH2
)
5
NaO3S
NaO3S
N
O
(CH2
)
5
SO3
Cl
COOH COOH
-
+
Compound (1)
A mixture of 4-[(5-carboxypentyl)oxy]-6-sulfo-1-(4-sulfobutyl)-2,3,3-trimethyl20 benz(e)indolium (internal salt and disodium salt) (9 g; 15 mmol), 2-chloro-1-formyl3-(hydroxymethylene)-1-cyclohexene (1.30 g; 7.50 mmol), and sodium acetate
(3g; 36.6 mmol) in a 60/30 mixture of acetic acid and acetic anhydride is heated
under reflux for 10 minutes. The reaction mixture is cooled to room temperature
and the precipitate is separated by filtration and washed with diethyl ether to give
25 4.33 g (yield: 43.9%) of a green solid. The crude product is purified by column
flash chromatography (inverse phase silica gel C18, acetonitrile 0-25% / water).
14
[41] Example 2:
[Chem. 20]
SO3Na
N
O
(CH2
)
5
NaO3S
NaO3S
N
O
(CH2
)
5
SO3
OMe
COONa COONa
-
+
Compound (2)
5 Sodium methylate (440 mg; 7.6 mmol) is added to compound (1) (1 g; 0.76 mmol)
in solution in 500 mL of methanol. The reaction mixture is heated under reflux for
16 h and concentrated under vacuum, and then filtered. The residue obtained is
washed with cold methanol and with acetone and dried under vacuum to give
450 mg of a green solid (yield: 45%). The crude product is purified by column flash
10 chromatography (inverse phase silica gel C18, acetonitrile 0-25% / water).
[42] Example 3:
[Chem. 21]
SO3Na
N
O
(CH2
)
5
NaO3S
NaO3S
N
O
(CH2
)
5
SO3
SMe
COONa COONa
-
+
Compound (3)
15 MeSNa (106 mg; 1.5 mmol) is added to compound (1) (400 mg; 0.30 mmol) in
solution in 20 mL of a 50/50 mixture of methanol/NMP (N-methyl-2-pyrrolidone).
The reaction mixture is heated under reflux for 4 h, and then diethyl ether (20 mL)
is added to the mixture. The precipitate is filtered and washed with the same
solvent to give 254 mg of crude product (yield: 61%; sulfur odor). The crude
20 product is purified by column flash chromatography (inverse phase silica gel C18,
acetonitrile 0-25% / water).
[43] Example 4:
[Chem. 22]
15
SO3Na
N
NaO3S
NaO3S
N
SO3
Cl
-
+
Compound (4)
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-
5 cyclohexene (0.40 g; 2.35 mmol), and sodium acetate (0.9 g; 11 mmol) in a 50/20
mixture of acetic acid and acetic anhydride is heated under reflux for 15 minutes.
The precipitate is separated by filtration, washed with ethanol and acetone and
dried under vacuum to give 1.6 g (yield: 63.8%) of a brick-red powder. The crude
product is purified by column flash chromatography (inverse phase silica gel C18,
10 acetonitrile 0-25% / water).
[44] Example 5:
[Chem. 23]
SO3Na
N
NaO3S
NaO3S
N
SO3
O
COOK
-
+
Compound (5)
15 8 mL of 1M methanolic KOH, 16 mL of DMSO and compound (4) (500 mg;
0.25 mmol) are added to 3-(4-hydroxyphenyl)propionic acid (660 mg; 4 mmol).
The reaction mixture is stirred at room temperature for 8h, and then 150 mL of
ethyl acetate is added dropwise. The precipitate is separated by filtration, washed
with ethanol and acetone and dried under vacuum to give 260 mg (yield: 45%) of a
20 green powder. The crude product is purified by column flash chromatography
(inverse phase silica gel C18, acetonitrile 0-25% / water).
[45] Example 6:
[Chem. 24]
16
SO3Na
N
NaO3S
NaO3S
N
SO3
NH
COOK
-
+
Compound (6)
4-Aminohydrocinnamic acid (816 mg; 4.9 mmol), 25 mL of DMSO and
triethylamine (500 mg; 4.9 mmol) are added to compound (4) (520 g; 0.49 mmol).
5 The reaction mixture is stirred at room temperature for 8h, and then 200 mL of
acetone is added dropwise. The precipitate is separated by filtration, washed with
acetone and dried under vacuum to give 430 mg (yield: 74%) of a red powder. The
crude product is purified by column flash chromatography (inverse phase silica gel
C18, acetonitrile 0-25% / water).
10 [46] Example 7:
[Chem. 25]
SO3Na
N
NaO3
S
NaO3S
N
SO3
S
COOK
-
+
Compound (7)
1 mL of 1M methanolic KOH, 16 mL of DMSO and compound (4) (500 mg;
15 0.25 mmol) are added to 4-mercaptohydrocinnamic acid (91 mg; 0.5 mmol). The
reaction mixture is stirred at room temperature for 30 minutes, and then 50 mL of
ethyl acetate is added dropwise. The precipitate is separated by filtration, washed
with ethanol and acetone and dried under vacuum to give 310 mg (yield: 54%) of a
green powder. The crude product is purified by column flash chromatography
20 (inverse phase silica gel C18, acetonitrile 0-25% / water).
17
[47] Example 8: Comparison of a compound according to the invention and a
fluorescent agent of the prior art (ICG) for in vivo imaging of mammary tumors
ICG (or indocyanine green / Infracyanine) is a fluorescent agent of the prior art,
already approved for use in humans for evaluation of cardiac and hepatic function,
5 as well as in ophthalmology, for retinal diseases. It is also undergoing evaluation in
many clinical trials throughout the world for guidance of surgery during tumoral
exereses, or mapping of the ganglia draining the tumors, by near infrared imaging.
ICG was compared with compound (2) according to the invention, synthesis of
which is described above in example 2; this compound is called CJ215 in this
10 study.
The study included 30 mice in total, distributed in three groups. The tumoral grafts
were all carried out with 50 000 cells 4T1-Dendra2 /20 μl injected in 2 mammary
glands contralaterally for each of the mice.
[48] The injections of the biomarkers (compound 2 called CJ215 in this study
15 and ICG) were carried out on D9 post-tumoral grafting (to limit the appearance of
necrosis in the tumors).
The variation of the intensity of the fluorescence signals recorded for each of the
biomarkers over time was evaluated from the microscopy image. The capacity of
the two markers for producing a signal specifically localized to the tumor was
20 assessed quantitatively by calculating the ratio of the specific signal associated
with the tumor to the nonspecific signal in the surrounding tissues.
[49] The imaging protocol was carried out at times 2h, 24h, 48h, 4 and 6 days
post-injection for all the mice. All the images made at each acquisition time were
acquired on the IVIS Spectrum imager (Perkin Elmer) with the following
25 parameters:
For detection of the GFP form of Dendra2 (detection of the tumor):
- Excitation at 465 nm
- Emission between 520 and 580 nm
For detection of the biomarkers:
30 - Excitation at 745 nm
18
- Emission between 800 and 840 nm
The quantitative measurements were performed on the raw images, which had not
been deconvoluted. For the two fluorophors, the acquisition time was
parameterized in automatic mode. In this mode, the system determines the
5 acquisition time taken to reach the stipulated target value (6000 counts) in the time
allowed (fixed at 2 min).
[50] Fig. 1 reports the median values and standard deviations of the
tumor/abdomen intensity ratios as a function of time post-injection of CJ215 and
ICG.
10 Measurement of the ratio of the tumor/abdomen intensities illustrated in this figure
makes it possible to show that:
- the intensity ratios are significantly higher for compound 2 (CJ215) compared to
ICG, regardless of the time post-injection (from 1.5 times at 2h to more than 3
times at D+6), which translates into a capacity for identifying a specific signal in
15 the tumors earlier and more specifically with compound 2 (CJ215). These results
also indicate the possibility of very significantly improving the specificity of the
signal to the tumor by increasing the time between injection of compound 2
(CJ215) and imaging;
- the signal/noise ratio increases continuously for compound 2 (CJ215) up to 6
20 days post-injection, the last day of examination considered in this protocol. At this
stage, ICG is no longer observable in the tumors (starting from 48h). The great
stability of the intratumoral signal of compound 2 (CJ215), compared to the
surrounding tissues, which eliminate the product, thus offers an improved capacity
for identifying the tumors and thus contributes to significant improvement in the
25 fine delimitation of the tumoral margins, which is still problematic with ICG.
[51] Example 9: Comparison of two compounds according to the invention and
a fluorescent agent of the prior art (ICG) in ex vivo imaging of pancreatic tumors.
A model of orthotopic pancreatic adenocarcinoma in the mouse was developed.
The tumoral cells were amplified subcutaneously in SCID mice and the resultant
30 fragments were then implanted surgically in the pancreas of irradiated BALB/c
nude mice.
The development of the tumor was monitored in vivo by MRI (4.7T, PharmaScan,
19
Bruker Biospin) at three time points, D14, 28 and 36. The animals were subjected
to a weak fluorescence in order to minimize autofluorescence. Fluorescent
imaging was performed with a charge-coupled device (CCD) camera (PhotonRT,
BiospaceLab) with excitation at 700 nm and an emission filter at 770 nm.
5 After sessions of in vivo imaging performed at 2h, 48h and 164h, ex vivo
fluorescent images were acquired. The fluorescent compounds according to the
invention 2 (CJ215) and CJ319 (the structure of which is detailed below) were
injected intravenously at 2 mg/kg, 39 days after implantation of the tumor
fragments, whereas the average volumes of the tumors were about 70 mm³.
10 Indocyanine green (ICG), a dye widely used in the per-operative imaging of tumors,
was included as a control.
[Chem. 26]
(CJ319)
15 [52] The ex vivo fluorescence imaging described in Fig. 2 showed that 2 hours
after injection, the two fluorescent compounds according to the invention were
present in the pancreas and the tumor in almost equivalent amounts. However, 48
hours after injection, a clear preferential distribution was observed for the tumor,
both compounds producing a fluorescent signal about four times higher in the
20 tumor than in the surrounding pancreatic tissue. This effect persisted six days after
injection, although the signal decreased as time passed. In comparison,
indocyanine green did not show any specific accumulation in the pancreas or the
tumor.
These results show the superiority of the compounds of the invention relative to a
25 fluorescent agent of the prior art at the level of their specific distribution in a tumor
tissue.
20
20
Claims
1. A compound of formula (I)
[Chem. 27]
5 (I)
in which
n1 and n2 are each an integer from 0 to 15,
R1, R2, R3, R4, R5 and R6 are each selected independently from H, OH, SH, NH2,
SO3R10 and X-R11-Y,
10 R10 and R'10 being independently H, Na or K,
X, X' and X'' being independently O, S or NH,
R11, R'11 and R''11 being selected independently 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);
15 Y, Y' and Y'' being selected independently from H, halogen, COOR'10 or amide;
R7 and R8 each being selected independently from H, OH, SH, NH2, C1 to C15 alkyl,
and X'-R'11-Y';
R9 being selected from H, OH, SH, NH2 and X''-R''11-Y'',
said compound comprising at least one group X-R11-Y, X'-R'11-Y' or X''-R''11-Y''
20 with Y, Y' and/or Y'' which is COOR'10.
2. The compound as claimed in claim 1 for which R1, R2, R3, R4, R5 and R6 are not
all simultaneously H.
3. The compound as claimed in claim 1 or 2 selected from the compounds of the
following formulas:
25 [Chem. 28]
21
21
[Chem. 29]
5 in which R1, R2, R3, R4, R5, R6, R7, R8 and R9 are as defined in claim 1.
4. The compound according to one of the preceding claims selected from the
compounds of the following formulas
[Chem. 30]
,
10
[Chem. 31]
,
22
22
[Chem. 32]
in which R1, R2, R3, R4, R5, R6, R7, R8 and R9 are as defined in claim 1.
5 5. The compound according to one of the preceding claims selected from the
compounds of the following formulas
[Chem. 33]
10 [Chem. 34]
[Chem. 35]
23
23
[Chem. 36]
5
[Chem. 37]
[Chem. 38]
10
24
24
[Chem. 39]
[Chem. 40]
5
[Chem. 41]
.
6. A method of preparation of the compounds as claimed in one of claims 1 to 5
10 comprising a reaction step between:
[Chem. 42]
and
25
25
[Chem. 43]
.
7. A method for labeling tumor tissue with one of the compounds as claimed in one
of claims 1 to 5 or prepared as claimed in claim 6.
5 8. The use of one of the compounds as claimed in one of claims 1 to 5 or prepared
as claimed in claim 6 in a method for labeling tumor tissue.
9. The compound as claimed in one of claims 1 to 5 or prepared as claimed in
claim 6 or a composition comprising the compound as claimed in one of claims 1
to 5 or prepared as claimed in claim 6 for use thereof in a method for labeling
10 and/or detection of tumor tissue, and/or in the surgical treatment of tumors.
10. A method for detecting tumor tissue comprising a step of labeling tumor tissue
with one of the compounds as claimed in one of claims 1 to 5 or prepared as
claimed in claim 6, and a step of detection by medical fluorescence imaging or
fluorescence spectrometry.