Radiolabeled-pegylation of ligands for use as imaging agents

• US 20070031328A1
• Filed: 06/26/2006
• Published: 02/08/2007
• Est. Priority Date: 06/24/2005
• Status: Abandoned Application

• Current Assignee: Trustees Of The University Of Pennsylvania (University of Pennsylvania)
• Original Assignee: Trustees Of The University Of Pennsylvania (University of Pennsylvania)
• Inventors: Kung, Hank
• Application Number:
  US11/474,489
• Publication Number:
  US 20070031328A1
• Time in Patent Office: Days
• US Class Current: 424/1.110
• CPC Class Codes: A61K 47/60 the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
• CPC Class Codes: A61K 51/04 Organic compounds
• CPC Class Codes: A61K 51/0453 having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
• CPC Class Codes: A61K 51/0455 having six-membered rings with one nitrogen as the only ring hetero atom
• CPC Class Codes: C07B 2200/05 Isotopically modified compounds, e.g. labelled
• CPC Class Codes: C07C 213/08 by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
• CPC Class Codes: C07D 213/64 attached in position 2 or 6
• CPC Class Codes: C07D 277/66 with aromatic rings or ring systems directly attached in position 2
• CPC Class Codes: C07D 471/04 Ortho-condensed systems

Abstract

The present invention is directed to a method of using radiolabeled ethylene glycol (n=1) (EG) or polyethylene glycol (n=from 2 to 10) (PEG) as a labeling group moiety on compounds that can be useful for imaging tissues. Specifically, the EG or PEG moiety preferably contains a radiofluorine (¹⁸F), and is covalently bonded to a ligand (L). The L portion of the molecule can be any molecule appropriate for covalently bonding with the radiolabeled EG or PEG moiety and subsequent use as an imaging agent. In particular, the imaging agent is preferably an agent suitable for administering to a mammal and detecting by PET or SPECT imaging.

Claims

1. A method of imaging amyloid deposits comprising,

a) administering to a mammal an amount of an imaging agent, said agent comprising a Ligand (L) that binds amyloid deposits covalently attached to a moiety (X′

), and having the following Formula IV,

wherein,

X′

is selected from the group consisting of hydrogen, hydroxy, C_1-4 alkoxy, halogen, radiohalogen,

wherein Q is a halogen or radiohalogen, and a chelating moiety bound to a radio-metal;

R^a, R^b, R^d, R^c, R^g and R^h are, in each instance, independently selected from the group consisting of hydrogen, hydroxy, C_1-4 alkoxy, C_1-4 alkyl, and hydroxy(C_1-4)alkyl;

m is an integer from 0 to 5; and

n is an integer from 1 to 10;

b) allowing sufficient time for said agent to become associated with one or more amyloid deposits in said mammal; and

c) detecting said agent associated with said one or more amyloid deposits;

provided,

that one of X′

or Q either contains a radiohalogen or radiometal as permitted, or (L) is covalently bonded to a radiohalogen;

that in Formula IV, when m is zero, L is other than;

or a pharmaceutically acceptable salt thereof, wherein;

A is selected from the group consisting of;

wherein R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are in each instance independently selected from the group consisting of hydrogen, hydroxy, amino, methylamino, dimethylamino, C_1-4 alkoxy, C_1-4 alkyl, and hydroxy(C_1-4)alkyl;

and

wherein n is an integer between 1 and 6; and

R⁷ and R⁸ are in each instance independently selected from the group consisting of hydrogen, hydroxy, amino, methylamino, dimethylamino, C_1-4alkoxy, C_1-4 alkyl, and hydroxy(C_1-4)alkyl;

R¹ is selected from the group consisting of;

a. NR^a′

R^b′

, wherein R^a′

and R^b′

are independently hydrogen, C_1-4 alkyl or (CH₂)_dX, where X is halogen, and d is an integer between 1 and 4,

b. hydroxy,

c. C_1-4 alkoxy, and

d. hydroxy(C_1-4)alkyl.

2. The method of claim 1, wherein said ligand (L) has the following structure:

wherein,

R¹ and R^1′

, are in each instance, independently selected from the group consisting of hydrogen, halogen, radiohalogen, C_1-4 alkyl, hydroxy, C_1-4 alkoxy, hydroxy(C_1-10)alkyl, amino(C_2-4)alkyl, halo(C_1-4)alkyl, C_6-10 aryl, haloarylalkyl, and —

NR^d′

R^e′

, wherein R^d′

and R^e′

, in each instance, is independently selected from the group consisting of;

hydrogen, C_1-4 alkyl and halo(C_1-4)alkyl, or R^d′

and R^e′

are taken together with the nitrogen to which they are attached to form a 5- to 7-member heterocyclic ring optionally having O, S or NR⁶ in said ring, where R⁶ is hydrogen or C_1-4 alkyl.

3. The method of claim 1, wherein said ligand (L) has the following structure:

wherein

R¹ and R^1′

, are in each instance, independently selected from the group consisting of;

hydrogen, halogen, radiohalogen, C_1-4 alkyl hydroxy, C_1-4 alkoxy, hydroxy(C_1-10)alkyl, amino(C_2-4)alkyl, halo(C_1-4)alkyl, C_6-10 aryl, haloarylalkyl, and —

NR^d′

R^e′

, wherein R^d′

and R^e′

, in each instance, is independently selected from the group consisting of;

hydrogen, C_1-4 alkyl and halo(C_1-4)alkyl, or R^d′

and R^e′

are taken together with the nitrogen to which they are attached to form a 5- to 7-member heterocyclic ring optionally having O, S or NR⁶ in said ring, where R⁶ is hydrogen or C_1-4 alkyl;

q is an integer from 0 to 3;

Z is O, S or N; and

Y is N or —

CH.

4. The method of claim 3, wherein q is 0 or 1.

5. The method of claim 1, wherein said ligand (L) has the following structure:

wherein,

G, B and D are CH or N,

provided that at least one no more than two of G, B and D is N; and

R¹ and R^1′

, are in each instance, independently selected from the group consisting of hydrogen, halogen, radiohalogen, C_1-4 alkyl, hydroxy, C_1-4 alkoxy, hydroxy(C_1-10)alkyl, amino(C_2-4)alkyl, halo(C_1-4)alkyl, C_6-10 aryl, haloarylalkyl, and —

NR^d′

R^e′

, wherein R^d′

and R^e′

, in each instance, is independently selected from the group consisting of;

hydrogen, C_1-4 alkyl and halo(C_1-4)alkyl, or R^d′

and R^e′

are taken together with the nitrogen to which they are attached to form a 5- to 7-member heterocyclic ring optionally having O, S or NR⁶ in said ring, where R⁶ is hydrogen or C_1-4 alkyl.

6. The method of claim 1, wherein said ligand (L) has the following structure:

wherein,

R¹ and R^1′

are, in each instance, independently selected from the group consisting of;

hydrogen, halogen, radiohalogen, C_1-4 alkyl, hydroxy, C_1-4 alkoxy, hydroxy(C_1-10)alkyl, amino(C_2-4)alkyl, halo(C_1-4)alkyl, C_6-10 aryl, haloarylalkyl, and —

NR^dR^e, wherein R^d and R^e, in each instance, is independently selected from the group consisting of;

hydrogen, C_1-4 alkyl and halo(C_1-4)alkyl, or R^d and R^e are taken together with the nitrogen to which they are attached to form a 5- to 7-member heterocyclic ring optionally having O, S or NR⁶ in said ring, where R⁶ is hydrogen or C_1-4 alkyl;

R^x and R^y, in each instance, is independently selected from the group consisting of hydrogen, C_1-4 alkyl, amino(C_2-4)alkyl, halo(C_1-4)alkyl, C_6-10 aryl, haloarylalkyl, and —

NR^d′

R^e′

, wherein R^d′

and R^e′

, in each instance, is independently selected from the group consisting of hydrogen, C_1-4 alkyl and halo(C_1-4)alkyl, or R^d′

and R^e′

are taken together with the nitrogen to which they are attached to form a 5- to 7-member heterocyclic ring optionally having O, S or NR⁶ in said ring, where R⁶ is hydrogen or C_1-4 alkyl.

7. The method of claim 1, wherein said ligand (L) has the following structure:

wherein,

R¹ and R^1′

are, in each instance, independently selected from the group consisting of hydrogen, halogen, radiohalogen, C_1-4 alkyl, hydroxy, C_1-4 alkoxy, hydroxy(C_1-10)alkyl, amino(C_2-4)alkyl, halo(C_1-4)alkyl, C_6-10 aryl, haloarylalkyl, and —

NR^d′

R^e′

, wherein R^d′

and R^e′

, in each instance, is independently selected from the group consisting of;

hydrogen, C_1-4 alkyl and halo(C_1-4)alkyl, or R^d′

and R^e′

are taken together with the nitrogen to which they are attached to form a 5- to 7-member heterocyclic ring optionally having O, S or NR⁶ in said ring, where R⁶ is hydrogen or C_1-4 alkyl.

8. The method of claim 1, wherein said ligand (L) has the following structure:

wherein,

R¹ and R^1′

are, in each instance, independently selected from the group consisting of hydrogen, halogen, radiohalogen, C_1-4 alkyl, hydroxy, C_1-4 alkoxy, hydroxy(C_1-10)alkyl, amino(C_2-4)alkyl, halo(C_1-4)alkyl, C_6-10 aryl, haloarylalkyl, and —

NR^d′

R^e′

, wherein R^d′

and R^e′

, in each instance, is independently selected from the group consisting of;

hydrogen, C_1-4 alkyl and halo(C_1-4)alkyl, or R^d′

and R^e′

are taken together with the nitrogen to which they are attached to form a 5- to 7-member heterocyclic ring optionally having O, S or NR⁶ in said ring, where R⁶ is hydrogen or C_1-4 alkyl.

9. The method of claim 1, wherein said ligand (L) has the following structure:

wherein,

n is an integer from one to six;

at least one, no more than three, of A₁, A₂, A₃, A₄ and A₅ is N, the others are —

CH or —

CR² as permitted;

R¹ and R², in each instance, are independently selected from the group consisting of hydrogen, C_1-4 alkyl, hydroxy, C_1-4 alkoxy, hydroxy(C_1-10)alkyl, amino(C_2-4)alkyl, halo(C_1-4al)yl, C_6-10 aryl, haloarylalkyl, and NR^a′

R^b′

(CH₂)_p—

,

wherein p is an integer from 0 to 5, and R^a′

and R^b′

, in each instance, is independently selected from the group consisting of;

hydrogen, C_1-4 allyl and halo(C_1-4)alkyl, or R^a′

and R^b′

are taken together with the nitrogen to which they are attached to form a 5- to 7-member heterocyclic ring optionally having O, S or NR⁶ in said ring, where R⁶ is hydrogen or C_1-4 alkyl are independently hydrogen, C_1-4 alkyl or (CH₂)_dX, where X is halogen, and d is an integer from 1 to 4, and

R⁷ and R⁸ are in each instance independently selected from the group consisting of hydrogen, hydroxy, amino, methylamino, dimethylamino, C_1-4 alkoxy, C_1-4 alkyl, and hydroxy(C_1-4)alkyl.

10. The method of claim 1, wherein said radiohalogen is selected from the group consisting of ¹⁸F, ¹³¹I, ¹²⁵I, ¹²³I, ¹²⁴I, ⁷⁷Br and ⁷⁶Br.

11. The method of claim 10, wherein said radiohalogen is ¹⁸F.

INSERT:

11a. The method of claim 1, wherein X′

is a chelate bound to a radio-metal of Technetium, Copper, Indium, or Gallium.

12. The method of claim 1, further comprising:

d) measuring the distribution of said agent within said mammal by positron emission tomography.

13. The method of claim 1, further comprising:

d) measuring the distribution of said agent within said mammal by single photon emission tomography.

14. The method of claim 1, wherein X′

is a N₂S₂ type chelating moiety bound to a radiometal.

15. The method of claims 1, 13 or 14, wherein said radiometal is 99m-Tc.

16. The method of claim 1, wherein said amyloid deposit is located in the central nervous system of said mammal.

17. The method of claim 1, wherein said amyloid deposit is located in the brain of said mammal.

21. The method of claim 1, wherein X′

is F or ¹⁸F.

22. The method of claim 1, wherein X′

is a chelating moiety bound to a radio-metal selected from the group consisting of Technetium, Copper, Indium, Gallium or Rhenium.

23. The method of claim 1, wherein said ligand (L) has the following structure:

wherein,

R¹ and R^1′

, are in each instance, independently selected from the group consisting of hydrogen, halogen, radiohalogen, C_1-4 alkyl, hydroxy, C_1-4 alkoxy, hydroxy(C_1-10)alkyl, amino(C_2-4)alkyl, halo(C_1-4)alkyl, C_6-10 aryl, haloarylalkyl, and —

NR^d′

R^e′

, wherein R^d′

and R^e′

, in each instance, is independently selected from the group consisting of;

hydrogen, C_1-4 alkyl and halo(C_1-4)alkyl, or R^d′

and R^e′

are taken together with the nitrogen to which they are attached to form a 5- to 7-member heterocyclic ring optionally having O, S or NR⁶ in said ring, where R⁶ is hydrogen or C_1-4 alkyl.

24. The method of claim 1, wherein said ligand (L) has the following structure:

wherein

R¹ and R^1′

, are in each instance, independently selected from the group consisting of;

hydrogen, halogen, radiohalogen, C_1-4 alkyl hydroxy, C_1-4 alkoxy, hydroxy(C_1-10)alkyl, amino(C_2-4)alkyl, halo(C_1-4)alkyl, C_6-10 aryl, haloarylalkyl, and —

NR^d′

R^e′

, wherein R^d′

and R^e′

, in each instance, is independently selected from the group consisting of;

hydrogen, C_1-4 alkyl and halo(C_1-4)alkyl, or R^d′

and R^e′

are taken together with the nitrogen to which they are attached to form a 5- to 7-member heterocyclic ring optionally having O, S or NR⁶ in said ring, where R⁶ is hydrogen or C_1-4 alkyl;

q is an integer from 0 to 3;

Z is O, S or N; and

Y is N or —

CH.

25. The method of claim 1, wherein said ligand (L) has the following structure:

wherein,

G, B and D are CH or N,

provided that at least one no more than two of G, B and D is N; and

R¹ and R^1′

, are in each instance, independently selected from the group consisting of hydrogen, halogen, radiohalogen, C_1-4 alkyl, hydroxy, C_1-4 alkoxy, hydroxy(C_1-10)alkyl, amino(C_2-4)alkyl, halo(C_1-4)alkyl, C_6-10 aryl, haloarylalkyl, and —

NR^d′

R^e′

, wherein R^d′

and R^e′

, in each instance, is independently selected from the group consisting of;

hydrogen, C_1-4 alkyl and halo(C_1-4)alkyl, or R^d′

and R^e′

are taken together with the nitrogen to which they are attached to form a 5- to 7-member heterocyclic ring optionally having O, S or NR⁶ in said ring, where R⁶ is hydrogen or C_1-4 alkyl.

26. The method of claim 1, wherein said ligand (L) has the following structure:

wherein,

R¹ and R^1′

are, in each instance, independently selected from the group consisting of hydrogen, halogen, radiohalogen, C_1-4 alkyl, hydroxy, C_1-4 alkoxy, hydroxy(C_1-10)alkyl, amino(C_2-4)alkyl, halo(C_1-4)alkyl, C_6-10 aryl, haloarylalkyl, and —

NR^d′

R^e′

, wherein R^d′

and R^e′

, in each instance, is independently selected from the group consisting of hydrogen, C_1-4 alkyl and halo(C_1-4)alkyl, or R^d′

and R^e′

are taken together with the nitrogen to which they are attached to form a 5- to 7-member heterocyclic ring optionally having O, S or NR⁶ in said ring, where R⁶ is hydrogen or C_1-4 alkyl.

27. The method of claim 1, wherein said ligand (L) has the following structure:

n is an integer from one to six;

at least one, no more than three, of A₁, A₂, A₃, A₄ and A₅ is N, the others are —

CH or —

CR²as permitted;

R¹ and R², in each instance, are independently selected from the group consisting of hydrogen, halogen, radiohalogen, C_1-4 alkyl hydroxy, C_1-4 alkoxy, hydroxy(C_1-10)alkyl, amino(C_2-4)alkyl, halo(C_1-4)alkyl, C_6-10 aryl, haloarylalkyl, and NR^a′

R^b′

(CH₂)_p—

,

wherein p is an integer from 0 to 5, and R^a′

and R^b′

, in each instance, is independently selected from the group consisting of;

hydrogen, C_1-4 alkyl and halo(C_1-4)alkyl, or R^a′

and R^b′

are taken together with the nitrogen to which they are attached to form a 5- to 7-member heterocyclic ring optionally having O, S or NR⁶ in said ring, where R⁶ is hydrogen or C_1-4 alkyl are independently hydrogen, C_1-4 alkyl or (CH₂)_dX, where X is halogen, and d is an integer from 1 to 4, and

R⁷ and R⁸ are in each instance independently selected from the group consisting of hydrogen, hydroxy, amino, methylamino, dimethylamino, C_1-4 alkoxy, C_1-4 alkyl, and hydroxy(C_1-4)alkyl.

28. The method of claim 1, wherein said ligand (L) has the following structure:

wherein,

n is an integer from one to six;

R¹ and R^1′

, in each instance, are independently selected from the group consisting of hydrogen, halogen, radiohalogen, C_1-4 alkyl, hydroxy, C_1-4 alkoxy, hydroxy(C_1-10)alkyl, amino(C_2-4)alkyl, halo(C_1-4)alkyl, C_6-10 aryl, haloarylalkyl, and NR^a′

R^b′

(CH₂)_p—

,

wherein p is an integer from 0 to 5, and R^a′

and R^b′

, in each instance, is independently selected from the group consisting of;

hydrogen, C_1-4 alkyl and halo(C_1-4)alkyl, or R^a′

and R^b′

are taken together with the nitrogen to which they are attached to form a 5- to 7-member heterocyclic ring optionally having O, S or NR⁶ in said ring, where R⁶ is hydrogen or C_1-4 alkyl are independently hydrogen, C_1-4 alkyl or (CH₂)_dX, where X is halogen, and d is an integer from 1 to 4, and

R⁷ and R⁸ are in each instance independently selected from the group consisting of hydrogen, hydroxy, amino, methylamino, dimethylamino, C_1-4 alkoxy, C_1-4 alkyl, and hydroxy(C_1-4)alkyl.

29. The method of claim 1, wherein said ligand (L) has the following structure:

wherein,

n is an integer from one to six;

R¹ and R^1′

, in each instance, are independently selected from the group consisting of hydrogen, halogen, radiohalogen, C_1-4 alkyl, hydroxy, C_1-4 alkoxy, hydroxy(C_1-10)alkyl, amino(C_2-4)allyl, halo(C_1-4)alkyl, C_6-10 aryl, haloarylalkyl, and NR^a′

R^b′

(CH₂)_p—

,

wherein p is an integer from 0 to 5, and R^a′

and R^b′

, in each instance, is independently selected from the group consisting of;

hydrogen, C_1-4 alkyl and halo(C_1-4)alkyl, or R^a′

and R^b′

are taken together with the nitrogen to which they are attached to form a 5- to 7-member heterocyclic ring optionally having O, S or NR⁶ in said ring, where R⁶ is hydrogen or C_1-4 alkyl are independently hydrogen, C_1-4 alkyl or (CH₂)_dX where X is halogen, and d is an integer from 1 to 4, and

R³, R⁴, R⁵ and R⁶ are in each instance independently selected from the group consisting of hydrogen, hydroxy, amino, methylamino, dimethylamino, C_1-4 alkoxy, C_1-4 alkyl, and hydroxy(C_1-4)alkyl.

18. A method of preparing a radiolabeled ligand comprising,

a) contacting a ligand (L-(CR^aR^b)_m), wherein R^a, R^b and m are as described above, said ligand containing a first reactive group, with a compound having the following Formula I,

wherein n is an integer from 1 to 10, optionally from 2 to 10;

Y′

is a third reactive group, and X is a second reactive group such that said first reactive group reacts with said second reactive group or the carbon to which it is attached to form a compound of Formula II,

b) contacting a compound of Formula II with a reagent (Z) to prepare a compound of Formula III,

wherein Z is a leaving group;

and

c) contacting a compound of Formula III with a radiohalogenating agent, wherein a radiolabeled ligand of Formula IV as described above is prepared.

19. In a method of imaging amyloid deposits comprising:

a) administering to a mammal a first ligand capable of binding amyloid deposits in the brain;

b) allowing sufficient time for said first ligand to become associated with one or more amyloid deposits in said mammal; and

c) detecting said first ligand associated with said amyloid deposits;

the improvement comprising covalently attaching to said first ligand a group to provide a second ligand having attached thereto a radiolabel suitable for imaging without a substantial increase in the lipophilicity of said, first ligand said group having the following structure;

wherein R^a, R^b, R^d, R^d, R^g, R^h, m, n are as described above, and X′

is selected from the group consisting of a radiohalogen,

wherein Q is a radiohalogen, and a chelating moiety bound to a radio-metal;

provided,

that if m is zero, said first ligand is other than;

or a pharmaceutically acceptable salt thereof, wherein;

A is selected from the group consisting of;

wherein R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are in each instance independently selected from the group consisting of hydrogen, hydroxy, amino, methylamino, dimethylamino, C_1-4 alkoxy, C_1-4 alkyl, and hydroxy(C_1-4)alkyl;

and

wherein n is an integer between 1 and 6; and

R⁷ and R⁸ are in each instance independently selected from the group consisting of hydrogen, hydroxy, amino, methylamino, dimethylamino, C_1-4 alkoxy, C_1-4 alkyl, and hydroxy(C_1-4)alkyl;

R¹ is selected from the group consisting of;

a NR^a′

R^b′

, wherein R^a′

and R^b′

are independently hydrogen, C_1-4 alkyl or (CH₂)_dX, where X is halogen, and d is an integer between 1 and 4,

b. hydroxy,

c. C_1-4alkoxy, and

d. hydroxy(C_1-4)alkyl.

20. A pharmaceutical composition comprising, (a) a compound capable of binding amyloid deposits, having a relatively low rate of transfer across a blood-brain barrier and having a core structure L1, L1′

, L2, L2′

, L3, L3′

, L4, L5 L6, L6′

, L7, L7′

, L₈ or L9 as described herein, the improvement comprising covalently attaching a group (Z) to said compound to provide imaging compounds having increased rates of transfer across a blood-brain barrier, wherein (Z) has the following formula;

wherein R^a, R^b, R^d, R^c, R^g, R^h, m, n and X′

are as described above; and

(b) pharmaceutically acceptable diluents or excipients.