Tumor imaging compounds

• US 20050192458A1
• Filed: 04/24/2003
• Published: 09/01/2005
• Est. Priority Date: 04/30/2002
• Status: Active Grant

• Current Assignee: Emory University
• Original Assignee: Emory University
• Inventors: Goodman, Mark M., McConathy, Jonathan
• Granted Patent: US 7,544,715 B2
• Time in Patent Office: Days
• US Class Current: 562/400
• CPC Class Codes: A61K 51/04 Organic compounds
• CPC Class Codes: A61K 51/0478 complexes from non-cyclic ligands, e.g. EDTA, MAG3
• CPC Class Codes: A61K 51/0487 Metallocenes, i.e. complexes based on a radioactive metal complexed by two cyclopentadienyl anions
• CPC Class Codes: C07B 2200/05 Isotopically modified compounds, e.g. labelled
• CPC Class Codes: C07C 229/20 the carbon skeleton being further substituted by halogen atoms or by nitro or nitroso groups
• CPC Class Codes: C07C 229/22 the carbon skeleton being further substituted by oxygen atoms
• CPC Class Codes: C07F 13/005 Compounds without a metal-carbon linkage

Abstract

The invention provides novel amino acid compounds of use in detecting and evaluating brain and body tumors. These compounds combine the advantageous properties of α-aminoisobutyric acid (AIB) analogs namely, their rapid uptake and prolonged retention in tumors with the properties of halogen sustituents, including certain useful halogen isotopes such as fluorine-18, iodine-123, iodine-124, iodine-125, iodine-131, bromine-75, bromine-76, bromine-77, bromine-82, astatine-210, astatine-211, and other astatine isotopes. In addition the compounds can be labeled with technetium and rhenium isotopes using known chelation complexes. The amino acid compounds disclosed herein have a high specificity for target sites when administered to a subject in vivo. Preferred amino acid compounds include [¹⁸F] FAMP, ([¹⁸F]5a) and [¹⁸F]N-MeFAMP, ([¹⁸F]5b). The invention further features pharmaceutical compositions comprised of an α-amino acid moiety attached to eiher a four, five or a six member carbon-chain ring. The labeled amino acid compounds are useful as imaging agents in detecting and/or monitoring tumors in a subject by Positron Emission Tomography (PET) and Single Photon Emission Computer Tomography (SPECT).

Claims

1. An amino acid analog having the general structure

2. The compound of claim 1, wherein R₁ and R₂ are R₃.

3. The compound of claim 1, wherein x is 0

y is 1

z is 2

q is 1

m is 0 and j is 0.

4. The compound of claim 3, wherein X is ¹⁸F or ¹²³I.

5. The compound of claim 3, wherein X is ¹⁸F.

6. The compound of claim 1, wherein R₁ and R₂ are R₃,

x is 0 or 1

y is 2

z is 4

q is 1

m and j are 0 and X is ¹⁸F or ¹²³I.

7. The compound of claim 6, wherein x is 1 and X is ¹⁸F.

8. The compound of claim 6, wherein x is 0 and X is ¹²³I.

9. The compound of claim 6, wherein x is 1 and X is ¹²³I.

10. The compound of claim 1, wherein R1 and R2 are R3,

x is 0

y is 1

z is 2

q is 0

m is 1

n is 1

j is 0 and X is ¹⁸F or ¹²³I.

11. The compound of claim 10, wherein X is ¹⁸F.

12. A compound according to claim 1 wherein R₁ and R₂ are R₃,

x is 1

y is 1

z is 1

q is 0

m and j are 0, and

X is ¹⁸F or ¹²³I.

13. A compound according to claim 12 wherein X is ¹²³I.

14. A compound according to claim 1 wherein R1 and R2 are R₃,

x is 0

y is 1

z is 2

q is 1

m is 1

n is 1

j is 1, and

X is ¹⁸F, or ¹²³I.

15. The compound of claim 14 wherein X is ¹²³I.

16. A compound according to claim 1 wherein R₁ and R₂ are R₃,

x is 0

y is 1

z is 2

q is 0

m is 0

j is 1, and

X is ¹⁸F, or ¹²³I.

17. The compound of claim 16 wherein X is ¹²³I.

18. A compound according to claim 1 wherein R1 and R2 are R₃,

x is 0 or 1

y is 2

z is 4

q is 1

m is 1

n is 1

j is 1, and

X is ¹⁸F, or ¹²³I.

19. The compound of claim 18 wherein X is ¹⁸F.

20. The compound of claim 18 wherein X is ¹²³I.

21. A compound according to claim 1, wherein R₁ and R₂ are R₃,

x is 0 or 1

y is 2

z is 4

q is 0

m is 0

j is 1, and

X is ¹⁸F, or ¹²³I.

22. The compound of claim 21 wherein X is ¹⁸F.

23. The compound of claim 21 wherein X is ¹²³I.

24. A compound of claim 1 wherein R₁ and R₂ are not R₃.

25. A compound according to claim 24 wherein X is ¹⁸F.

26. A compound according to claim 1 wherein R₁ is X—

CH═

CH—

,

R₂ is H, y is 1 and z is 2.

27. The compound of claim 26 wherein X is ¹²³I.

45. The compound of claim 1, wherein R₁ is ¹⁸F, R₂ is H, y is 1, z is 2, and R₄ is —

CH₃.

47. A method of in situ tumor imaging by positron emission tomography comprising:

administering to a subject suspected of having a tumor an image-generating amount of a compound according to claim 1, and measuring the distribution of the compound in the subject by positron emission tomography.

28-44. -44. (canceled)

46. An amino acid analog having the general structure

48. An amino acid analog having the general structure

49. The compound of claim 48 wherein Z is

50. The compound of claim 48 wherein Z is

51. The compound of claim 48 wherein Z is

52. The compound of claim 48 wherein Z is