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 Tc-99m-SC-05-L-1 and Tc-99m- 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 Tc-99m-SC-05-L-1 or Tc-99m-SC-05-N-1 single-photon emission computed tomography/computed tomography was conducted in tumor-bearing rodents and compared to F-18-fluoro-2-deoxy-d-glucose (F-18-FDG) positron emission tomography/magnetic resonance imaging (a reference technology). Results: The radiochemical purities of Tc-99m-SC-05-L-1 and Tc-99m-SC-05-N-1 were greater than 99% (n = 10). Tc-99m-SC-05-L-1 had higher cell/media ratios than Tc-99m-SC-05-N-1 in OVCAR-3 ER (+) cells. The cell uptake of Tc-99m-SC-05-L-1 was blocked 80% by estrone indicating an ER-mediated process occurred. Tc-99m-SC-05-N-1 was further selected for in vivo imaging studies due to higher maximum tolerated dose and superior water solubility than Tc-99m-SC-05-L-1. Tc-99m-SC-05-N-1 showed higher tumor uptake and tumor/muscle count density ratios than F-18-FDG in tumor-bearing rodents. Conclusion: Tc-99m-SC-05-N-1 showed better differential diagnosis of ovarian tumors than F-18-FDG, indicating great promising in chelator-tamoxifen conjugate for ER pathway-directed systems imaging.