Labeled evans blue dye derivative for in vivo serum albumin labeling

Patent metadata

Field	Value
Publication number	US-2016287730-A1
Application number	US-201514675364-A
Country	US
Kind code	A1
Filing date	Mar 31, 2015
Priority date	Mar 31, 2015
Publication date	Oct 6, 2016
Grant date	—

Abstract

Disclosed is a compound of formula (I):

wherein L, R 1 -R 5 , A, B, M, and n are as defined in the specification, as well as a method of preparing the compound. Also disclosed are a method of blood-pool imaging in a mammal and a method of imaging a lymph node in a mammal, comprising use of the compound.

First claim

1 . A compound of formula (I):

wherein L is a linker group selected from aryl, biaryl, heteroaryl, and biheteroaryl, wherein the aryl, biaryl, heteroaryl, or biheteroaryl is optionally substituted with one or more groups selected from alkyl, halo, hydroxy, and alkyloxy,
wherein A is selected from a bond, C═O, and C 1 -C 6 alkyl,
wherein B is a chelating group selected from 1, 4, 7-triazacyclononane-N,N′,N″-triacetic acid, 1, 4, 7,10-tetrazacyclononane-N,N′,N″-triacetic acid, triethylenetetramine, diethylenetetramine pentaacetic acid, and hydrazinonicotinamide,
wherein R 1 -R 5 are independently selected from hydrogen, OH, NH 2 , and SO 3 H,
wherein n is 0 or 1, and
wherein M is selected from 18 F-AlF, 60 Cu, 61 Cu, 62 Cu, 64 Cu, 67 Cu, 68 Ga, 86 Y, 89 Zr, 111 In, 99m Tc, 186 Re, 188 Re, Gd 3+ , and Mn 2+ .

2 . The compound of claim 1 , wherein L is biphenyl, optionally substituted with one or more groups selected from alkyl, halo, hydroxy, and alkyloxy.

3 . The compound of claim 2 , wherein A is a bond.

4 . The compound of claim 3 , wherein B is 1, 4, 7-triazacyclononane-N,N′,N″-triacetic acid.

5 . The compound of claim 4 , wherein n is 0 and the compound is:

6 . The compound of claim 1 , wherein n is 1 and M is 18 F-AlF, 64 Cu, or 68 Ga.

7 . An imaging composition comprising a compound of formula (I) and a pharmaceutically acceptable carrier.

8 . The imaging composition of claim 7 , wherein the pharmaceutical composition further comprises Evans blue dye.

9 . A method of blood-pool imaging in a mammal, comprising administering to the mammal a compound of claim 1 , wherein
n is 1, M is selected from 18 F-AlF, 60 Cu, 61 Cu, 62 Cu, 64 Cu, 67 Cu, 68 Ga, 86 Y, 89 Zr, 111 In, 99m Tc, 186 Re, 188 Re, Gd 3+ , and Mn 2+ , and PET imaging the mammal.

10 . The method of claim 9 , which involves imaging a heart of the mammal.

11 . The method of claim 10 , wherein the imaging is performed at least twice.

12 . The method of claim 11 , which involves measuring a ventricular ejection volume.

13 . The method of claim 9 , which involves imaging a vascularized muscular tissue.

14 . The method of claim 13 , which involves detecting a vascular leakage.

15 . The method of claim 9 , which involves imaging a hepatic hemangioma.

16 . A method of imaging a lymph node in a mammal, comprising administering to the mammal a compound of claim 1 , wherein
n is 1, M is selected from 18 F-AlF 60 Cu, 61 Cu, 62 Cu, 64 Cu, 67 Cu, 68 Ga, 86 Y, 89 Zr, 111 In, 99m Tc, 186 Re, 188 Re, Gd 3+ , and Mn 2+ , and imaging the mammal.

17 . The method of claim 16 , wherein the imaging is PET imaging.

18 . The method of claim 17 , wherein the lymph node is a sentinel lymph node.

19 . The method of claim 16 , comprising coadministering to the mammal Evans blue dye.

20 . The method of claim 19 , wherein the imaging is performed visually.

21 . A method of preparing a compound of formula (IV):

wherein L is a linker group selected from aryl, biaryl, heteroaryl, and biheteroaryl, wherein the aryl, biaryl, heteroaryl, or biheteroaryl is optionally substituted with one or more groups selected from alkyl, halo, hydroxy, and alkyloxy, wherein M is selected from 18 F-AlF, 64 Cu, or 68 Ga, and wherein n is 0 or 1, comprising the steps of:
(i) reacting a his amino compound of the formula: H 2 N-L-NH 2 wherein L is aryl, biaryl, heteroaryl, and biheteroaryl, wherein the aryl, biaryl, heteroaryl, or biheteroaryl is optionally substituted with one or more groups selected from alkyl, halo, hydroxy, and alkyloxy, with 1, 4, 7-triazacyclononane-N,N′,N″-triacetic acid to form a compound of formula (II):

(iii) reacting the compound of formula (II) with a diazotization reagent to form a compound of formula (III):

 and
(iv) reacting the compound of formula (III) with 4-amino-5-hydroxynaphthalene-1,3-disulfonic acid to form the compound of formula (IV).

22 . The method of claim 21 , further comprising a step of reacting the compound of formula (IV) with MX 2 , wherein M is selected from 18 F-AlF, 64 Cu, or 68 Ga and wherein X is a halogen, to provide a compound of formula (V):

23 . The method of claim 22 , wherein the compound of formula (V) is:

Assignees

• Us Health
• Us Health

Inventors

• Chen Xiaoyuan
• Lang Lixin
• Niu Gang

Classifications

• A61K51/0482 Primary

  chelates from cyclic ligands, e.g. DOTA · CPC title

• C07B59/004

  Acyclic, carbocyclic or heterocyclic compounds containing elements other than carbon, hydrogen, halogen, oxygen, nitrogen, sulfur, selenium or tellurium · CPC title

• C09B45/00

  Complex metal compounds of azo dyes · CPC title

• C09B29/30

  Amino naphtholsulfonic acid · CPC title