Synthesis and composition of amino acid linking groups conjugated to compounds used for the targeted imaging of tumors
The present disclosure relates to compounds that are useful as near-infrared fluorescence probes, wherein the compounds include i) a pteroyl ligand that binds to a target receptor protein, ii) a dye molecule, and iii) a linker molecule that comprises an amino acid or derivative thereof. The disclosure further describes methods and compositions for incorporating the compounds as used for the targeted imaging of tumors. Conjugation of the amino acid linking groups increase specificity and detection of the compound. Methods and compositions for use thereof in diagnostic imaging are contemplated.
1. A composition for use in diagnostic imaging of diseased ovarian tissue, abnormal ovarian tissue, ovarian tumor lesions, or lymph nodes with metastatic ovarian tumor cells or for use in determining response to surgical treatment of ovarian cancer wherein the composition comprises a compound having the formula:
or a pharmaceutically acceptable salt of said compound or isotope thereof, wherein:
X is a single amino acid or a single amino acid derivative thereof, wherein the single amino acid or single amino acid derivative contains an —OH, —NH 2 , or —SH functional group,
and Y is a dye that has a fluorescence excitation and emission spectra in the near infra-red range, wherein Y is represented by the formula:
wherein, R 1 is independently selected from the group consisting of O, S, N, and C, and R 2 is independently selected from the group consisting of CH 2 and CH 2 CH 2 .
2. The composition of claim 1 , wherein the single amino acid is selected from the group consisting of tyrosine, cysteine, serine, and lysine.
3. The composition of claim 2 , wherein the single amino acid of the compound is tyrosine.
4. The composition of claim 1 , wherein the single amino acid derivative is selected from the group consisting of a derivative of tyrosine, a derivative of cysteine, a derivative of serine and a derivative of lysine.
5. The method of claim 1 , wherein the diagnostic imaging is fluorescence-guided surgery or image-guided surgery.
6. The composition of claim 1 , further comprising a pharmaceutically acceptable carrier, excipient, or diluent.
7. The composition of claim 1 , wherein the diagnostic imaging comprises the steps of:
a) contacting the diseased ovarian tissue, abnormal ovarian tissue, ovarian tumor lesions, or lymph nodes with metastatic ovarian tumor cells with the composition;
b) allowing time for the compound to distribute within the diseased ovarian tissue, abnormal ovarian tissue, ovarian tumor lesions, or lymph nodes with metastatic ovarian tumor cells;
c) illuminating the diseased ovarian tissue, abnormal ovarian tissue, ovarian tumor lesions, or lymph nodes with metastatic ovarian tumor cells with an excitation light of a wavelength absorbable by the compound; and
d) detecting the optical signal emitted by the compound.
8. The composition of claim 7 , wherein the diseased ovarian tissue, abnormal ovarian tissue, ovarian tumor lesions, or lymph nodes with metastatic ovarian tumor cells comprises cancerous cells expressing a folate receptor.
9. The composition of claim 8 , wherein the diagnostic imaging further comprises the step of:
e) diagnosing the subject with ovarian cancer.
10. A method of performing image guided surgery on a subject having diseased ovarian tissue, abnormal ovarian tissue, ovarian tumor lesions, or lymph nodes with metastatic ovarian tumor cells, the method comprising:
a) administering to the subject a composition comprising a compound under conditions and for a time sufficient for the compound to bind and accumulate in diseased ovarian tissue, abnormal ovarian tissue, ovarian tumor lesions, or lymph nodes with metastatic ovarian tumor cells, the compound having the formula:
or a pharmaceutically acceptable salt of said compound or isotope thereof, wherein:
X is a single amino acid or a single amino acid derivative thereof, wherein the single amino acid or single amino acid derivative contains an —OH, —NH 2 , or —SH functional group,
and Y is a dye that has a fluorescence excitation and emission spectra in the near infra-red range, wherein Y is represented by the formula:
wherein, R 1 is independently selected from the group consisting of O, S, N, and C, and R 2 is independently selected from the group consisting of CH 2 and CH 2 CH 2 ,
b) illuminating the compound to visualize the compound bound to the diseased ovarian tissue, abnormal ovarian tissue, ovarian tumor lesions, or lymph nodes with metastatic ovarian tumor cells using infrared light; and
c) performing surgical resection of diseased ovarian tissue, abnormal ovarian tissue, ovarian tumor lesions, or lymph nodes with metastatic ovarian tumor cells that fluoresce upon excitation by the infrared light.
11. The method of claim 10 , wherein the single amino acid is selected from the group consisting of tyrosine, cysteine, serine, and lysine.
12. The method of claim 11 , wherein the single amino acid of the compound is tyrosine.
13. The method of claim 10 , wherein the single amino acid derivative is selected from the group consisting of a derivative of tyrosine, a derivative of cysteine, a derivative of serine, and a derivative of lysine.
14. A method of diagnosing ovarian cancer in a subject, the method comprising:
a) administering to the subject in need of diagnosis a composition comprising a compound under conditions and for a time sufficient for the compound to bind and accumulate in diseased ovarian tissue, abnormal ovarian tissue, ovarian tumor lesions, or lymph nodes with metastatic ovarian tumor cells, the compound having the formula:
or a pharmaceutically acceptable salt of said compound or isotope thereof, wherein:
X is a single amino acid or a single amino acid derivative thereof, wherein the single amino acid or single amino acid derivative contains an —OH, —NH 2 , or —SH functional group,
and Y is a dye that has a fluorescence excitation and emission spectra in the near infra-red range, wherein Y is represented by the formula:
wherein, R 1 is independently selected from the group consisting of O, S, N and C, and R 2 is independently selected from the group consisting of CH 2 and CH 2 CH 2 ,
b) illuminating the compound to visualize the compound bound to the diseased ovarian tissue, abnormal ovarian tissue, ovarian tumor lesions, or lymph nodes with metastatic ovarian tumor cells using infrared light;
c) measuring fluorescent signal from the illuminated compound bound to the diseased ovarian tissue, abnormal ovarian tissue, ovarian tumor lesions, or lymph nodes with metastatic ovarian tumor cells;
d) comparing the fluorescent signal measured in step c) with at least one control data set, wherein the at least one control data set comprises a fluorescent signal from the compound contacted with a biological sample that does not comprise diseased ovarian tissue, abnormal ovarian tissue, ovarian tumor lesions, or lymph nodes with metastatic ovarian tumor cells; and
e) diagnosing the subject with ovarian cancer based on step d).
15. The method of claim 14 , wherein the single amino acid is selected from the group consisting of tyrosine, cysteine, serine, and lysine.
16. The method of claim 15 , wherein the single amino acid of the compound is tyrosine.
17. The method of claim 14 , wherein the single amino acid derivative is selected from the group consisting of a derivative of tyrosine, a derivative of cysteine, a derivative of serine, and a derivative of lysine.