Nucleosides for imaging and treatment applications
First Claim
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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.
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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.
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Citations
12 Claims
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1. A method for assessing the response of tumors to treatment with a thymidylate synthase inhibitor, comprising the steps of:
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(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. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 12)
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.
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5. The method of claim 4, wherein the positron emitter is 18F or 11C.
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6. The method of claim 4, wherein the uridine analog is 18F-1-(2′
- -fluoro-2′
-deoxy-β
-D-arabinofuranosyl)-uracil.
- -fluoro-2′
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7. The method of claim 1 wherein the uridine analog comprises a compound of the following formula:
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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.
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8. The method according to claim 7 wherein W is a positron emitter.
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9. The method according to claim 7 wherein W is 18F.
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12. The method of claim 1, wherein the uridine analog is a mixture of enantiomers.
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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:
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(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. - View Dependent Claims (11)
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Specification