Breast and endometrial cancer are the most common invasive malignancies in women in the United States. Every year, more than 217,000 new breast and endometrial cancer diagnoses are made. Breast and endometrial cancer are sometimes classified into two subtypes based upon the expression of estrogen receptor (ER). In this project, we describe ER α/β- and GPR30-targeted steroidal and non-steroidal radioimaging agents for cancer imaging and diagnosis.

Selected steroidal estradiol derivatives and GPR30-targeted non-steroidal G1-derivatives were radiolabeled with gamma-emitting radionuclides ^99mTc and ¹¹¹In. Once radiobeling was accomplished, purification methods were developed and optimized to obtain highest specific activity and radiochemical purity. In vitro cellular binding analysis was performed on corresponding receptor-expressing cancer cells. Once the in vitro binding affinities were established the corresponding radiolabeled agents were tested in normal and tumor bearing animals. The ER α/β- and GPR30-targeted ^99mTc-labeled estradiol derivative was evaluated in healthy female C57BL/6 during defined phases of the estrus cycle. Biodistribution and NanoSPECT/CT imaging studies were performed on ER-expressing MCF-7 tumor-bearing mice and primary human endometrial tumor-bearing mice and on GPR30-expressing human endometrial Hec50Co tumor-bearing mice using GPR30 targeted ^99mTc and ¹¹¹In derivatives.

All the evaluated radiolabeled agents showed in vivo receptor specificity measured by the radiotracer with non-radioactive ligand. All the ^99mTc agents had high liver uptake and were slowly excreted mainly through the hepatobilary system, whereas the ¹¹¹In derivative had relatively higher uptake in the intestines and was rapidly excreted through hepatobiliary pathway. The G1 derivatives were metabolized within a few hours of injection as demonstrated by HPLC radiochromatograms of collected urine samples. MCF-7 tumors were visualized after injecting the ^99mTc-estradiol derivative whereas Hec50Co tumors were visualized after injecting ^99mTc-G1 and ¹¹¹In-G1 derivatives. In conclusion, we have synthesized and evaluated a series ER α/β and GPR30 targeted radioimaging agents. Although most compounds showed great promise for standard biodistribution studies, further structural modifications are needed to optimize for better imaging characteristics and targeting.