Imaging tumor glycolysis by non-invasive measurement of pyruvate kinase M2
A novel pyruvate kinase M2 (PKM2)-specific activator, [ 11 C]DASA-23 and derivatives thereof, and methods for their rapid synthesis are provided. The probes are particularly useful in methods for the non-invasive positron emission tomography (PET) detection and imaging of PKM2 expression in subcutaneous and orthotopic tumors. [ 11 C]DASA-23 cell uptake correlates with PKM2 protein expression in cultured tumor cells and orthotopic tumors are delineated from the surrounding normal brain tissue in vivo.
1. A pyruvate kinase M2 activator precursor wherein said precursor is 4-((4-((2,6-difluorophenyl)sulfonyl)piperazin-1-yl)sulfonyl)phenol (I) having the formula:
2. A method of generating a pyruvate kinase M2 activator precursor, wherein said precursor is 4-((4-((2,6-difluorophenyl)sulfonyl)piperazin-1-yl)sulfonyl)phenol (I) and, wherein said method is according to scheme A:
3. A pharmaceutically acceptable probe composition comprising a Positron Emission Tomography (PET)-detectable radiolabelled probe, wherein said probe has the formula:
wherein R 1 is selected from the group consisting of: 11 C-methoxy, 18 F-fluoromethoxy-, 18 F-fluoroethoxy-, and 18 F-fluoropropoxy-.
4. The pharmaceutically acceptable probe composition according to claim 1 wherein said probe has the formula:
5. The pharmaceutically acceptable probe composition of claim 3 further comprising a pharmaceutically acceptable carrier.
6. A method of generating a radiolabelled probe, wherein said method is according to scheme B:
or according to scheme C:
wherein n is 1, 2, or 3.
7. A method of detecting a cell or a population of cells expressing pyruvate kinase M2, said method comprising:
(i) contacting a cell or population of cells with a pharmaceutically acceptable PET-detectable radiolabelled probe composition comprising at least one probe having a radionuclide and having the formula:
wherein R 1 is selected from the group consisting of: 11 C-methoxy, 18 F-fluoromethoxy-, 18 F-fluoroethoxy-, and 18 F-fluoromethoxy-; and
(ii) detecting pyruvate kinase M2-specific binding of the radionuclide-containing probe within the cell or population of cells by detecting the presence of the radionuclide in the cell or population of cells.
8. The method of claim 7 , wherein the probe has the formula:
9. The method of claim 7 , further comprising the step of delivering the pharmaceutically acceptable probe composition to a human or non-human animal.
10. The method of claim 7 , wherein in step (ii), the detection of the radionuclide is by Positron Emission Tomography (PET).
11. A method of detecting in a human or non-human animal a localized population of cancer cells expressing pyruvate kinase M2 (PKM2), said method comprising the steps of:
(i) administering to a human or non-human animal a pharmaceutically acceptable composition comprising a radiolabeled pyruvate kinase M2 (PKM2)-specific probe having the formula:
wherein R 1 is selected from the group consisting of: 11 C-methoxy, 18 F-fluoromethoxy-, 18 F-fluoroethoxy-, and 18 F-fluoromethoxy-; and
(ii) identifying a tissue in the animal or human host, wherein the amount of the detectable label in the tissue is greater than in other tissues of the host, thereby identifying a population of cancer cells expressing pyruvate kinase M2.
12. The method of claim 11 , wherein the probe has the formula:
13. The method of claim 11 , wherein the radiolabeled pyruvate kinase M2 (PKM2)-specific probe is detected by Positron Emission Tomography (PET) scanning.
14. The method of claim 11 , wherein the tissue is a glioma of the brain.