Chelation-Tamoxifen Conjugates for Imaging of Estrogen Receptors
Background:
The differential diagnosis of estrogen receptor-positive (ER+) pathway-activated systems by using a labeled antiestrogen helps to select the patients for optimal response to endocrine therapy and to discontinue the treatment when resistance occurs. The authors' purpose was to synthesize chelator-tamoxifen conjugates for imaging ER (+) diseases.
Materials and Methods:
A hydroxypropyl linker was incorporated between either cyclam or cyclam diacetic acid and tamoxifen analog to produce SC-05-L-1 (Z-1-(1,4,8,11-tetraazacyclotetradecan-1-yl)-3-((5-(4-(2-(diethylamino)ethoxy)phenyl)-4,5-diphenylpent-4-en-1-yl)oxy)propan-2-ol) and SC-05-N-1 (Z-2,2′-(4-(3-((5-(4-(2-(diethylamino)ethoxy)phenyl)-4,5-diphenylpent-4-en-1-yl)oxy)-2-hydroxy-propyl)-1,4,8,11-tetraazacyclotetradecane-1,8-diyl)diacetic acid), respectively.
In vitro
cell uptake and cell/media ratios of
99m
Tc-SC-05-L-1 and
99m
Tc- SC-05-N-1 in ER (+) ovarian cancer cells (TOV-112D and OVCAR3) were performed. To ascertain the specificity of cell uptake, the cell uptake was blocked with estrone.
In vivo
99m
Tc-SC-05-L-1 or
99m
Tc-SC-05-N-1 single-photon emission computed tomography/computed tomography was conducted in tumor-bearing rodents and compared to
18
F-fluoro-2-deoxy-
d
-glucose (
18
F-FDG) positron emission tomography/magnetic resonance imaging (a reference technology).
Results:
The radiochemical purities of
99m
Tc-SC-05-L-1 and
99m
Tc-SC-05-N-1 were greater than 99% (
n
= 10).
99m
Tc-SC-05-L-1 had higher cell/media ratios than
99m
Tc-SC-05-N-1 in OVCAR-3 ER (+) cells. The cell uptake of
99m
Tc-SC-05-L-1 was blocked 80% by estrone indicating an ER-mediated process occurred.
99m
Tc-SC-05-N-1 was further selected for
in vivo
imaging studies due to higher maximum tolerated dose and superior water solubility than
99m
Tc-SC-05-L-1.
99m
Tc-SC-05-N-1 showed higher tumor uptake and tumor/muscle count density ratios than
18
F-FDG in tumor-bearing rodents.
Conclusion:
99m
Tc-SC-05-N-1 showed better differential diagnosis of ovarian tumors than
18
F-FDG, indicating great promising in chelator-tamoxifen conjugate for ER pathway-directed systems imaging.
