Vitamin-targeted imaging agents
The invention relates to compounds and methods for targeting radionuclide-based imaging agents to cells having receptors for a vitamin, or vitamin receptor binding derivative or analog thereof, by using such a vitamin as the targeting ligand for the imaging agent. The invention provides a compound of the formula for use in such methods. In the compound, V is a vitamin that is a substrate for receptor-mediated transmembrane transport in vivo, or a vitamin receptor binding derivative or analog thereof, L is a divalent linker, R is a side chain of an amino acid, M is a cation of a radionuclide, n is 1 or 0, K is 1 or 0, and the compound can be in a pharmaceutically acceptable carrier therefor. The vitamin-based compounds can be used to target radionuclides to cells, such as a variety of tumor cell types, for use in diagnostic imaging of the targeted cells.
1. A compound of the formula
wherein V is a vitamin or V is a receptor-binding analog or derivative of the vitamin, wherein V is a substrate for receptor-mediated transmembrane transport in vivo;
L is a divalent linker;
R is a side chain of an amino acid;
M is a cation of a radionuclide;
n is 1 or 0; and
k is 1 or 0.
2. The compound of claim 1 wherein V is a vitamin selected from the group consisting of folate, riboflavin, thiamine, vitamin B 12 , and biotin, or a vitamin receptor binding derivative or analog thereof.
3. The compound of claim 1 wherein the radionuclide is selected from the group consisting of isotopes of gallium, indium, copper, technetium, and rhenium.
4. The compound of claim 3 wherein the radionuclide is an isotope of technetium.
5. The compound of claim 1 wherein V is folate, or a folate receptor binding analog or derivative thereof.
6. A composition for diagnostic imaging comprising a compound of the formula
wherein V is a vitamin or V is a receptor-binding analog or derivative of the vitamin, wherein V is a substrate for receptor-mediated transmembrane transport in vivo;
L is a divalent linker;
R is a side chain of an amino acid;
M is a cation of a radionuclide;
n is 1 or 0; and
a pharmaceutically acceptable carrier therefor.
7. The composition of claim 6 wherein V in the compound is a vitamin selected from the group consisting of folate, riboflavin, thiamine, vitamin B 12 , and biotin, or a vitamin receptor binding derivative or analog thereof.
8. The composition of claim 6 wherein the radionuclide in the compound is selected from the group consisting of isotopes of gallium, indium, copper, technetium, and rhenium.
9. The composition of claim 8 wherein the radionuclide in the compound is an isotope of technetium.
10. The composition of claim 6 adapted for parenteral administration.
11. The compound of claim 6 wherein V is folate, or a folate receptor binding analog or derivative thereof.
12. A method of imaging a population of cells in an animal wherein said cells are characterized by a vitamin receptor on the surface of said cells, the method comprising the steps of
administering to the animal an effective amount of a composition comprising a compound of the formula
wherein V is the vitamin or V is a vitamin receptor binding derivative or analog of the vitamin, specific for said cell surface vitamin receptor;
L is a divalent linker;
R is a side chain of an amino acid;
M is a cation of a radionuclide;
n is 1 or 0; and
a pharmaceutically acceptable carrier therefor; and
monitoring the biodistribution of said compound in the animal.
13. The method of claim 12 wherein V in the compound is a vitamin selected from the group consisting of folate, riboflavin, thiamine, vitamin B 12 , and biotin, or a vitamin receptor binding derivative or analog thereof.
14. The method of claim 12 wherein the radionuclide in the compound is selected from the group consisting of isotopes of gallium, indium, copper, technetium, and rhenium.
15. The method of claim 14 wherein the radionuclide in the compound is an isotope of technetium.
16. The method of claim 12 wherein the composition is administered parenterally to the animal.
17. The method of claim 12 wherein V is folate, or a folate receptor binding analog or derivative thereof.
18. A compound of the formula
wherein V is a vitamin or V is a receptor-binding analog or derivative of the vitamin, wherein V is a substrate for receptor-mediated transmembrane transport in vivo;
L is a divalent linker;
R is a side chain of an amino acid;
M is a cation of a radionuclide;
n is 1 or 0; and
k is 1 or 0.
19. A composition for diagnostic imaging comprising a compound of the formula
wherein V is a vitamin or V is a receptor-binding analog or derivative of the vitamin, wherein V is a substrate for receptor-mediated transmembrane transport in vivo;
L is a divalent linker;
R is a side chain of an amino acid;
M is a cation of a radionuclide;
n is 1 or 0; and
a pharmaceutically acceptable carrier therefor.
20. A method of imaging a population of cells in an animal wherein said cells are characterized by a vitamin receptor on the surface of said cells, the method comprising the steps of
administering to the animal an effective amount of a composition comprising a compound of the formula
wherein V is the vitamin or V is a receptor-binding analog or derivative of the vitamin, specific for said cell surface vitamin receptor;
L is a divalent linker;
R is a side chain of an amino acid;
M is a cation of a radionuclide;
n is 1 or 0; and
a pharmaceutically acceptable carrier therefor; and
monitoring the biodistribution of said compound in the animal.
21. The compound of claim 18 wherein V is a vitamin selected from the group consisting of folate, riboflavin, thiamine, vitamin B 12 , and biotin, or a vitamin receptor binding derivative or analog thereof.
22. The compound of claim 18 wherein the radionuclide is selected from the group consisting of isotopes of gallium, indium, copper, technetium, and rhenium.
23. The compound of claim 22 wherein the radionuclide is an isotope of technetium.
24. The compound of claim 18 wherein V is folate, or a folate receptor binding analog or derivative thereof.
25. The composition of claim 19 wherein V is a vitamin selected from the group consisting of folate, riboflavin, thiamine, vitamin B 12 , and biotin, or a vitamin receptor binding derivative or analog thereof.
26. The composition of claim 19 wherein the radionuclide is selected from the group consisting of isotopes of gallium, indium, copper, technetium, and rhenium.
27. The composition of claim 26 wherein the radionuclide is an isotope of technetium.
28. The composition of claim 19 wherein V is folate, or a folate receptor binding analog or derivative thereof.
29. The composition of claim 19 adapted for parenteral administration.
30. The method of claim 20 wherein V is a vitamin selected from the group consisting of folate, riboflavin, thiamine, vitamin B 12 , and biotin, or a vitamin receptor binding derivative or analog thereof.
31. The method of claim 20 wherein the radionuclide is selected from the group consisting of isotopes of gallium, indium, copper, technetium, and rhenium.
32. The method of claim 31 wherein the radionuclide is an isotope of technetium.
33. The method of claim 20 wherein V is folate, or a folate receptor binding analog or derivative thereof.
34. The method of claim 20 wherein the composition is administered parenterally to the animal.