Liver-targeting agents and their synthesis

• US 8,552,163 B2
• Filed: 09/27/2010
• Issued: 10/08/2013
• Est. Priority Date: 09/25/2009
• Status: Active Grant

• Current Assignee: Institute Of Nuclear Energy Research Atomic Energy Council Executive Yuan, Johns Hopkins University
• Original Assignee: Institute Of Nuclear Energy Research Atomic Energy Council Executive Yuan, Johns Hopkins University
• Inventors: Lee, Reiko Takasaka, Lee, Yuan-Chuan, Wang, Mei-Hui, Lin, Wuu-Jyh
• Primary Examiner(s): Olson, Eric S
• Assistant Examiner(s): Wang, Zhengfu
• Application Number:
  US12/891,004
• Publication Number:
  US 20110077386A1
• Time in Patent Office: 1,107 Days
• Field of Search: 536/17.9, 562/572
• US Class Current: 536/17.9
• CPC Class Codes: C07H 15/04 attached to an oxygen atom of the saccharide radical

Abstract

This invention provides novel liver targeting agents and their synthetic methods. A liver targeting agent, with a lysine based nitrilotriacetic acid structure as backbone which acquires multivalency with saccharide groups, to bind with a galactosamine chain or lactose chain is disclosed. In particular, only one amino acid L-lysine is involved to provide trivalency. All carboxyl groups in N^ε-benzyloxycarbonyl-N^α-dicarboxymethyl-L-lysine can be conjugated with three glycosides of ahGalNAc or ahLac in one step. This invention also provides a hexa-lactoside. In particular, the TFA-AHA-Asp was used to conjugate 2 molecules of NTA(ahLac)₃. This invention also provides a method for adding a spacer between NTA and DTPA. The extended hepatocyte-specific glyco-ligand has higher ¹¹¹In-radiolabelling yield than those non-extended.

Claims

1. A liver targeting agent comprising a lysine-based nitrilotriacetic acid structure which acquires multivalency by linking carboxyl groups in the nitrilotriacetic acid structure with ahLac (6-aminohexyl-β

-lactose), ahGalNAc (6-amino hexyl-β

-N-acetylgalactosamine), or GahGalNAc (Glycyl-aminohexyl-acetylgalactosamine).

2. The liver targeting agent according to claim 1, wherein the carboxyl groups in the nitrilotriacetic acid structure link with ahLac (6-aminohexyl-β

-lactose).

3. The liver targeting agent according to claim 1, wherein the structure of the lysine-based nitrile triacetic acid is α

-dicarboxylmethyl-L-lysine.

4. The liver targeting agent according to claim 2, wherein the agent comprising two molecules of trivalent lactoside linked through the carboxyl groups of an aspartic acid or glutamic acid.

5. The liver targeting agent according to claim 2, wherein the agent is AHA-Asp[DCM-Lys(ahLac)₃]₂, wherein DCM is dicarboxylmethyl, AHA is aminohexanoyl.