NOVEL LIVER-TARGETING AGENTS AND THEIR SYNTHESIS

• US 20110077386A1
• Filed: 09/27/2010
• Published: 03/31/2011
• 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, YUAN-CHUAN, LEE, REIKO TAKASAKA, LIN, WUU-JYH, WANG, MEI-HUI
• Granted Patent: US 8,552,163 B2
• Time in Patent Office: Days
• 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 nitrilo triacetic 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 moles 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 nitrilo triacetic acid structure which acquires multivalency with one or more saccharide groups to bind with a galactosamine chain or lactose chain.

2. The liver targeting agent according to claim 1, wherein the one or more saccharide groups is selected from the group consisting of ah-Lac, ahGalNAc, and GahGalNAc.

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

-dicarboxylmethyl-L-lysine.

4. The liver targeting agent according to claim 1, further comprising a lactose chain connected in series, wherein two molecules of a three-chain lactoside are connected together with aspartic acid or glutamic acid in series, that is, two molecules of ε

-Z-α

-DCM-Lys (ah-Lac)₃ are connected together with aminohexanoic aspartic acid (AHA-Asp) in series, to form AHA-Asp[DCM-Lys(ah-Lac)₃]₂ (hexa-Lactoside).

5. A method of synthesizing a trivalent ligand in one step, the method comprising conjugating lysine based NTA with three glycosides of GalNAc or Lac.

6. The method of claim 5, further comprising synthesizing NTA by N^ε

-protected lysine carboxymethylated with glycolic acid (CHOCOOH) under reductive conditions or with bromoacetic acid to obtain a “

nitrilo-triacetic acid”

group.

7. The method of claim 5, wherein only one amino acid, L-lysine, is used to provide trivalency.

8. The method of claim 5, further comprising designing Cbz-NTA to link aminohexyl-GalNAc or aminohexyl-Lac.

9. The method of claim 5, further comprising synthesizing GalNAc glycoside by reacting TFA-ah with an ozazoline derivative of galactosamine per-O-acetate.

10. The method of claim 5, further comprising synthesizing Lac glycoside by reacting TFA-ah with acetobromo β

-lactose.

11. A method of synthesizing hexa-lactoside, comprising:

conjugating NTA-(ahLac)₃ with TFA-ah modified Asp [CF₃CONH(CH₂)₅CONHCH(CH₂COOH)COOH] in DMSO in the presence of DCC/1-OH-Bt; and

performing de-N-trifluoroacetylation in aqueous solution containing 10% ethanol and 10% triethylamine (TEA) overnight at room temperature.

12. The method of claim 11, further comprising preparing TFA-AHA-Asp by conjugating L-aspartic acid dibenzyl ester p-toluenesulfonate salt with TFA-ah in the presence of DCC/1-OH-Bt in dry DMF.

13. The method of claim 11, further comprising synthesizing TFA-ah by reacting 6-aminohexanol and trifluoroacetate in one pot at room temp with stirring 5 hr, and then in the cold for 14 hr.

14. A method of adding a spacer between NTA and a possible chelator.

15. The method of claim 14, wherein the spacer is aminohexanol.

16. The method of claim 14, wherein the DTPA-AHA-NTA(Gah-GalNAc)₃ with such longer spacer has a higher ¹¹¹In radio-labeling yield than DTPA-NTA(Gah-GalNAc)₃.

17. The method of claim 14, wherein the chelator is DTPA.