Optical imaging agents targeting inflammation

Patent metadata

Field	Value
Publication number	US-2020368373-A1
Application number	US-201916968272-A
Country	US
Kind code	A1
Filing date	Feb 21, 2019
Priority date	Feb 21, 2018
Publication date	Nov 26, 2020
Grant date	—

Abstract

The present invention relates to an optical imaging agent of formula (SIGNAL)n-SUPPORT-(L-BIOVECTOR)m, wherein: SUPPORT represents a physiologically acceptable chemical or biological substrate, with a particle size of between 1 and 100 nm, SIGNAL is a fluorophore, L is a linker of formula —C(X)—R1—Y—, with X being O, NH or S R1 being a (C1-C6)alkyl group, optionally R1 being a (C1-C6)alkyl group, optionally interrupted by 1 to 3 groups selected from —O—, —NH—, —C(O)—, —NHC(O)—, —(O)CNH—, —C(O)NH—N═C—, —N═C—, and (I), Y being NH or a —(O)CNH— group, and BIOVECTOR is a carbohydrate targeting markers of inflammation, advantageously selected from the group consisting of mannose, sialyl LewisX and derivatives thereof, n is greater than or equal to 0.5 and is less than 2, m is between 0 and 30, preferably between 1 and 30, more preferably between 5 and 20, diagnostic compositions comprising same and use thereof as a diagnostic agent (in vivo or ex vivo), or as contrast agent for image-guided surgery.

First claim

1 . Optical imaging agent of formula (SIGNAL) n -SUPPORT-(L-BIOVECTOR) m , wherein:
SUPPORT represents a physiologically acceptable chemical or biological substrate, with a particle size of between 1 and 100 nm, SIGNAL is a fluorophore, L is a linker of formula —C(X)—R 1 —Y—, with
X being O, NH or S,
R 1 being a (C 1 -C 6 )alkyl group, preferably a (C 3 -C 5 )alkyl group, optionally interrupted by 1 to 3 groups selected from —O—, —NH—, —C(O)—, —NHC(O)—, —(O)CNH—, —C(O)—NH—N═C—, —N═C—, and

Y being NH or —(O)CNH—, and

BIOVECTOR is a carbohydrate able to target markers of inflammation,
n is greater than or equal to 0.5 and is less than 2,
m is between 1 and 30,

or a pharmaceutically acceptable salt, solvate or hydrate thereof.

2 . The optical imaging agent of claim 1 , wherein SUPPORT is a protein.

3 . The optical imaging agent of claim 1 , wherein SUPPORT is an albumin with a particle size of between 1 and 100 nm.

4 . The optical imaging agent of claim 1 , wherein SIGNAL is of formula (I):

wherein
q is 0 or 1,
r is 0 or 1,
R b1 and R b2 are H or a C 1 -C 4 group, or are bridged to form a —CH 2 —CH 2 —CH 2 — alkylene group (only when q and r represent 1),
R a1 and R a2 are identical or different and are independently a (C 1 -C 6 )alkyl group, optionally substituted by a SO 3 − group, a SO 3 K group, a SO 3 Na group, or a COOH group, provided that not more than one of R a1 and R a2 is substituted by a SO 3 − group,
Ring A represents a C 5 -C 6 monocyclic aryl or heteroaryl group or a C 8 -C 12 fused bicyclic aryl or heteroaryl group,
provided that the compound of formula (I) comprises at least one SO 3 − or SO 3 Na group, but not more than one SO 3 − group, and that when the compound of formula (I) has an overall positive electric charge, it is provided as a salt, in particular a halogenide salt such as a chloride Cl − salt.

5 . The optical imaging agent of claim 1 , wherein X is NH and R 1 is a (C 1 -C 6 ) alkyl, optionally interrupted by a

group.

6 . The optical imaging agent of claim 1 , wherein BIOVECTOR is of formula (II):

wherein R 2 represents a (C 1 -C 6 )alkyl group, and X′ represents a heteroatom such as O, S or NH, or a compound of formula (III) or (IV)

wherein R is R 2 —X′, with R 2 being a (C 1 -C 6 )alkyl group and X′ being a heteroatom such as O, S or NH, and Rs is H, SO 3 K or SO 3 Na.

7 . The optical imaging agent of claim 1 , wherein BIOVECTOR is of formula (V), (VI) or (VII):

wherein R is R 2 —X′, with R 2 being a (C 1 -C 6 )alkyl group and X′ being a heteroatom such as O, S or NH.

8 . A diagnostic composition comprising at least one optical imaging agent according to claim 1 , a pharmaceutically acceptable salt, solvate or hydrate thereof, and at least one pharmaceutically acceptable excipient.

9 . An in vivo diagnostic method comprising administering to a patient in need thereof an effective amount of the optical imaging agent according to claim 1 .

10 . The in vivo diagnostic method according to claim 9 , comprising diagnosing diseases or conditions associated with inflammation.

11 . The in vivo diagnostic method according to claim 10 , wherein the disease or condition associated with inflammation is selected from stroke, renal failure or cancer.

12 . The in vivo diagnostic method according to claim 9 , wherein said method is applied to surgical resection of tumours in the patient and comprises the following further successive steps:
resecting the tumoral tissue identified prior to surgery in an area of interest; imaging the area of interest of the patient, to whom the effective amount of the optical imaging agent has been administered prior to surgery or during surgery, using an optical imaging device, so as to identify remaining tumoral tissues; when light signals are observed in the area of interest defining remaining tumoral tissues, proceeding with the resection of the identified remaining tumoral tissues; when no light signal is observed in the area of interest, not proceeding with any further resection in the area of interest.

13 . A method of imaging a biological tissue ex vivo, wherein said biological tissue comprises the optical imaging agent according to claim 1 , the method comprising applying optical or fluorescence imaging to said tissue.

14 . The method of claim 13 , wherein the biological tissue is a biopsy sample.

15 . The method of claim 13 , further comprising a step of diagnosing a disease or condition associated with inflammation from said optical or fluorescence imaging.

16 . The optical imaging agent of claim 1 , wherein SUPPORT is a human serum albumin with a particle size of between 1 and 100 nm.

17 . The optical imaging agent of claim 4 , wherein Ring A represents a C 5 -C 6 monocyclic aryl group or a C 8 -C 12 fused bicyclic aryl group, such as a phenyl or naphthyl group.

18 . The optical imaging agent of claim 4 , wherein Ring A is substituted by one SO 3 − or SO 3 Na group, provided that not more than one of R a1 and R a2 is substituted by a SO 3 − group.

19 . The optical imaging agent of claim 6 , wherein R 2 represents a (C 1 -C 4 )alkyl group and X′ represents NH.

Assignees

• Univ Sorbonne
• Institut National De La Sante Et De La Res Medicale
• Ecole Nat Superieure De Chimie De Paris
• Centre National De La Recherce Scient
• Univ Paris

Inventors

• Zhang Yongmin
• Bessodes Michel
• Seguin Johanne
• Mignet Nathalie
• Scherman Daniel

Classifications

• A61K49/0093

  Nanoparticle, nanocapsule, nanobubble, nanosphere, nanobead, i.e. having a size or diameter smaller than 1 micrometer, e.g. polymeric nanoparticle · CPC title

• A61K49/0091 Primary

  Microparticle, microcapsule, microbubble, microsphere, microbead, i.e. having a size or diameter higher or equal to 1 micrometer · CPC title

• A61K49/0052

  Small organic molecules (oligomers, polymers, dendrimers A61K49/0054) · CPC title

• A61K49/0056

  Peptides, proteins, polyamino acids · CPC title

• A61K49/0054

  Macromolecular compounds, i.e. oligomers, polymers, dendrimers · CPC title