Nucleosides for imaging and treatment applications

• US 6,683,045 B2
• Filed: 08/30/2001
• Issued: 01/27/2004
• Est. Priority Date: 10/30/1997
• Status: Expired due to Fees

• Current Assignee: United States Department Of Health And Human Services (Government of the United States of America)
• Original Assignee: United States Department Of Health And Human Services (Government of the United States of America)
• Inventors: Anderson, Lawrence, Collins, Jerry M., Klecker, Raymond W., Katki, Aspandiar G.
• Primary Examiner(s): Riley, Jezia
• Application Number:
  US09/941,571
• Publication Number:
  US 20020034473A1
• Time in Patent Office: 880 Days
• Field of Search: 514/1, 514/44, 424/1.11
• US Class Current: 514/1
• CPC Class Codes: C07H 19/06 Pyrimidine radicals
• CPC Class Codes: C07H 21/00 Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids

Abstract

Methods of diagnosing and/or of treating tumors by administering a nucleoside analogue which is activated by thymidylate synthase and/or thymidine kinase enzyme into a diagnostic or toxic metabolite, and uridine analogue compounds, and compositions of same having a pharmaceutically acceptable carrier. For diagnostic applications, compounds containing a label and methods of use of such compounds are described.

Claims

1. A method for assessing the response of tumors to treatment with a thymidylate synthase inhibitor, comprising the steps of:

(a) administering a uridine analogue selected by a method comprising the steps of;

providing a uridine analogue unsubstituted in the 5-position;

testing said uridine analog for activation by thymidylate synthase; and

selecting said uridine analog when found to be activated by thymidylate synthase;

wherein said uridine analogue is labeled with a positron emitter; and

(b) determining an extent of maximum thymidylate synthase inhibition and persistence of thymidylate synthase inhibition over time between doses by external imaging.

2. The method of claim 1 wherein the positron emitter is ¹⁸F or ¹¹C.

3. The method of claim 1 wherein the external imaging is accomplished using positron emission tomography.

4. The method of claim 1, wherein the uridine analogue comprises a compound of the following general formula:

wherein;

A=N, C;

B=H, hydroxy, halogen, acyl (C₁-C₆), alkyl (C₁-C₆), alkoxy (C₁-C₆)

D=O, S, NH₂; and

G=substituted or unsubstituted cyclic sugar, substituted or unsubstituted acyclic sugar, substituted or unsubstituted mono, di, or tri-phospho-cyclic-sugar phosphate;

substituted or unsubstituted mono, di, or tri-phospho-acyclic-sugar phosphate;

substituted or unsubstituted mono, di, or tri-phospho-cyclic sugar analogues, substituted or unsubstituted mono, di, or tri-phospho-acyclic sugar analogues wherein the substituents are alkyl (C₁-C₆), alkoxy (C₁-C₆), halogen.

5. The method of claim 4, wherein the positron emitter is ¹⁸F or ¹¹C.

6. The method of claim 4, wherein the uridine analog is ¹⁸F-1-(2′

-fluoro-2′

-deoxy-β

-D-arabinofuranosyl)-uracil.

7. The method of claim 1 wherein the uridine analog comprises a compound of the following formula:

wherein;

A=N, C;

B=H, hydroxy, halogen, acyl (C₁-C₆), alkyl (C₁-C₆), alkoxy (C₁-C₆)

D=0, S, NH₂,

at least one of W, X, Y, Z is a positron emitter having sufficient isotopic activity for imaging and the remainder of W, X, Y, Z=H, hydroxy, halogen, alkyl (C₁-C₆), substituted alkyl (C₁-C₆), alkoxy (C₁-C₆), substituted alkoxy (C₁-C₆);

J=C, S; and

K=O, C.

8. The method according to claim 7 wherein W is a positron emitter.

9. The method according to claim 7 wherein W is ¹⁸F.

12. The method of claim 1, wherein the uridine analog is a mixture of enantiomers.

10. A method for assessing the response of tumors to treatment with a combination of thymidylate synthase inhibitor and at least one additional compound with anti-tumor activity, comprising the steps of:

(a) administering a combination of a uridine analogue and at least one additional compound with anti-tumor activity, wherein said uridine analogue is selected by a method comprising the steps of;

providing a uridine analogue unsubstituted in the 5-position;

testing said uridine analog for activation by thymidylate synthase; and

selecting said uridine analog when found to be activated by thymidylate synthase;

wherein said uridine analogue is labeled with a positron emitter; and

(b) determining an extent of maximum thymidylate synthase inhibition and persistence of thymidylate synthase inhibition over time between doses by external imaging.

11. The method of claim 10, wherein said at least one additional compound with anti-tumor activity comprises a uridine analog.