Metal complexes with bisphosphonate useful as imaging agents
Provided herein are magnetic resonance imaging (MRI) contrast agents comprising a compound having a structure represented by: Y—X—Z, wherein, X is: Fe(III) or Mn(II), and Y and Z are each independently selected from pyrophosphate and bisphosphonate (e.g., 1-hydroxybisphosphonate), or a pharmaceutically acceptable hydrate and/or salt thereof. Methods of use of the MRI contrast agent are also provided.
1. A magnetic resonance imaging (MRI) contrast agent comprising a compound having a structure represented by:
Y—X—Z
wherein,
X is Mn(II) and Y and Z are each independently a bisphosphonate of the formula:
wherein: R 1 is —OH, and R 2 is selected from the group consisting of: H, alkyl, aminoalkyl, alkylaminoalkyl, arylalkyl, and heteroarylalkyl
wherein said compound has a stoichiometry of 1:2 (Mn(II):bisphosphonate);
wherein said compound is a salt comprising at least one alkali metal and at least one alkaline earth metal, and
wherein the contrast agent has a molecular weight of less than 2,000 daltons.
2. The MRI contrast agent of claim 1 , wherein the contrast agent has a molecular weight of less than 800 daltons.
3. The MRI contrast agent of claim 1 , wherein the compound is octahedral.
4. The MRI contrast agent of claim 1 , wherein the compound is a monohydrate or a dihydrate.
5. The MRI contrast agent of claim 1 , wherein the alkali metal comprises Na+ or K+.
6. The MRI contrast agent of claim 1 , wherein said bisphosphonate is etidronate.
7. The MRI contrast agent of claim 1 , comprising:
at least one water coordinated with said Mn(II).
8. The MRI contrast agent of claim 1 , wherein said MRI contrast agent has an r 2 relaxivity of 5 to 18 mM −1 sec −1 measured at 7 Tesla, 22 degrees Celsius, in 2 mM Tris buffered ddH 2 O, pH 7.0.
9. The MRI contrast agent of claim 1 , wherein said alkaline earth metal is selected from calcium and magnesium.
10. The MRI contrast agent of claim 9 , wherein said alkali metal comprises sodium.
11. The MRI contrast agent of claim 1 , wherein said compound is coupled to one or more therapeutic agents.
12. The MRI contrast agent of claim 11 , wherein said one or more therapeutic agents are covalently coupled to Y and/or Z.
13. A composition comprising the MRI contrast agent of claim 1 in a pharmaceutically acceptable carrier.
14. The composition of claim 13 , wherein said composition is formulated for intravenous or intraarterial administration.
15. The composition of claim 13 , wherein said pharmaceutically acceptable carrier is water or phosphate buffered saline.
16. The composition of claim 13 , wherein said composition has a pH of from 6.0 to 8.0.
17. The composition of claim 13 , wherein said composition has a pH of from 7.0 to 7.4.
18. A method of performing a magnetic resonance imaging (MRI) scan on a subject comprising administering the composition of claim 13 to said subject prior to and/or during said MRI scan.
19. A method of administering a therapeutic agent to a subject in need thereof, comprising administering the MRI contrast agent of claim 1 to said subject in a treatment effective amount.
20. The method of claim 19 , further comprising detecting the MRI contrast agent with MRI in said subject.