Compositions and methods for in vivo imaging

Patent metadata

Field	Value
Publication number	US-10010629-B2
Application number	US-201514806207-A
Country	US
Kind code	B2
Filing date	Jul 22, 2015
Priority date	May 17, 2010
Publication date	Jul 3, 2018
Grant date	Jul 3, 2018

Abstract

The present disclosure provides lipid-probe compounds, and compositions comprising the compounds. A subject lipid-probe compound is useful for various imaging applications, which are also provided.

First claim

What is claimed is:

1. A compound of the formula:
Q-L-X—Y

wherein Q is a lipid;
X is an optional leaving group;
L is a cleavable linker comprising a cleavable bond that provides for release of Y or X—Y following cleavage of the linker; and
Y comprises a detectable moiety that, after release, generates a direct or indirect detectable signal wherein Y is selected from a luciferin, an aminoluciferin, coelenterazine, a modified coelenterazine, a coelenterazine analog, a membrane permeant coelenterazine analog, a dihydroluciferin, a luciferin 6′ methylether, a luciferin 6′ chloroethylether;
wherein L is described by one of the following structures:

wherein:
n is 1, 2 or 3;
R 26 and R 51 are independently selected from O, S and NR, where R is hydrogen or alkyl;
T 1 is a single bond or a linking group that is bound to Q;
R 31 and R 52 are independently one or more groups, each R 31 and R 52 independently selected from H, an alkyl, an aliphatic, an amino, an aryl, an acyl, an alkoxy, an aryloxy, an acyloxy, a carbonyl, a cyano, a halogen, hydroxyl, a heterocyclic group, a nitro, a thio, a sulfinyl, a sulfonyl and trifluoromethyl; and
R 21 , R 22 , R 23 , R 24 , R 25 , R 32 , R 33 , R 41 , R 42 , R 43 , R 44 , R 45 , R 46 , R 53 and R 54 are independently selected from hydrogen, an alkyl, an aryl, a heterocyclic group and an amino acid sidechain group.

2. The compound of claim 1 , wherein:
Q is selected from an unsaturated fatty acid, a polyunsaturated fatty acid, a saturated fatty acid, an essential fatty acid, a trans fatty acid, a glycerolipid, a triglyceride, a diglyceride, a monoglyceride, a fatty acid, a sterol, an oxisterol, a cholesterol ester, cholesterol, a bile acid, a steroid hormone, a vitamin derived fatty acid, vitamin E, vitamin K, a phospholipid, a sphingolipid, a ganglioside, a prenol lipid, a carotinoid, and a ubiquinone.

3. The compound of claim 1 , wherein:
L comprises an enzyme substrate and is cleaved using an enzyme.

4. The compound of claim 1 , wherein:
L is susceptible to cleavage under particular physiological conditions selected from reducing conditions, oxidizing conditions, acidic pH, and basic pH.

5. The compound of claim 1 , wherein:
cleavage of the cleavable bond of linker L unmasks a functional group that triggers the release of Y or X—Y.

6. The compound of claim 1 , wherein:
upon cleavage of the cleavable bond of linker L, a nucleophilic moiety is unmasked, that provides for intramolecular reaction at an electrophilic site adjacent to the leaving group X leading to the release of X—Y.

7. The compound of claim 1 , wherein:
L is described by the structure:

wherein;
T 1 is a single bond or a linking group that is bound to Q; and
X is O or S.

8. The compound of claim 1 , wherein:
Y comprises:
a) an optionally substituted luciferin moiety, where luciferin moiety has one of the following structures:

wherein R 3 is hydrogen, alkyl or substituted alkyl;

b) an optionally substituted coelenterazine moiety, wherein coelenterazine has the structure:

wherein R 3 and R 4 are independently selected from hydrogen, an acyl, an acyloxy, and an acylamino;

c) the following structure:

wherein R 1 , R 2 , R 3 , and R 4 are independently H, alkyl, heteroalkyl, aryl, or combinations thereof, wherein the structure is attached to the linker via any one of R 1 , R 2 , R 3 and R 4 ;

d) an optionally substituted membrane-permeant coelenterazine moiety of one of the following structures:

wherein R 4 and R 5 are independently an alkyl, an aryl, an aralkyl, an alkoxy, or a heterocyclic group;

e) an optionally substituted membrane-permeant coelenterazine moiety of one of the following structures:

wherein p is an integer of about 1 to 20;

f) an optionally substituted membrane-permeant coelenterazine moiety of one of the following structures:

wherein R 1 , R 2 , and R 3 are independently an alkyl, an alkenyl, or an aralkyl;

g) an optionally substituted membrane-permeant coelenterazine moiety of one of the following structures:

wherein r is an integer of about 1 to 20;

h) an optionally substituted membrane-permeant coelenterazine moiety of one of the following structures:

wherein r is an integer of about 1 to 20; and
R 6 is an alkyl, an aryl, an aralkyl, or an alkoxyalkyl;

i) one of the following structures:

wherein R 2 is N or CH;
R 3 is hydrogen, a halo, an alkyl, an alkoxy, an amino, —CH 2 N═R, or CH 2 NRR′, wherein R is alkyl and R′ is alkyl; and
R 4 is hydrogen, alkyl or substituted alkyl;

j) one of the following structures:

wherein R 2 is N or CH; and R 3 is hydrogen, alkyl or substituted alkyl;

k) one of the following structures:

wherein R 2 is O or S;
R 3 is hydrogen, a halo, an alkyl, an alkoxy, an amino, —CH 2 N═R, or CH 2 NRR′, wherein R is alkyl and R′ is alkyl; and
R 4 is hydrogen, alkyl or substituted alkyl; or

l) one of the following structures:

wherein R 2 is N or CH;
R 3 is hydrogen, a halo, an alkyl, an alkoxy, an amino, —CH 2 N═R, or CH 2 NRR′, wherein R is alkyl and R′ is alkyl; and
R 4 is hydrogen, alkyl or substituted alkyl.

9. The compound of claim 1 , wherein:
release of Y produces a luciferin of one of the following structures:

wherein R 3 is hydrogen , alkyl or substituted alkyl; and R 4 is hydrogen, alkyl, substituted alkyl or alkoxy.

10. The compound of claim 1 , wherein:
Y comprises;
a) a contrast agent or a radioisotope suitable for use in imaging;
b) a detectable moiety that comprises 123 I (iodine), 18 F (fluorine), 99 Tc (technetium), 111 In (indium),

Assignees

• Univ California

Inventors

• Bertozzi Carolyn Ruth
• Stahl Andreas
• Fluitt Amy Helene
• Dubikovskaya Elena A
• Cohen Allison

Classifications

• C07D487/04

  Ortho-condensed systems · CPC title

• C07D277/64

  with only hydrocarbon or substituted hydrocarbon radicals attached in position 2 · CPC title

• C07D417/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• A61K49/0052 Primary

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

• A61K51/0453

  having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole · CPC title