IMAGING, BIODISTRIBUTION AND THERAPY POTENTIAL OF HALOGENATED TAMOXIFEN ANALOGS

Tamoxifen binds to estrogen receptors (ERs) and prevents breast cancer cell proliferation. This study is aimed at developing a ligand for imaging ER (+) breast tumors by positron emission tomography. (PET) or single photon emission computed tomography (SPECT). [F-18]-Labeled tamoxifen analogue ([F-18]FTX) was prepared in 30-40% yield and [I-131]-labeled tamoxifen analogue ([I-131]ITX) was prepared in 20-25% yield. In mammary tumor-bearing rats, the biodistribution of [F-18]FTX at 2 h showed a tumor uptake value (% injected dose/gram tissue) of 0.41+/-0.07; when rats were pretreated with diethylstilbestrol (DES), the value changed to 0.24+/-0.017. [I-131]ITX at 6 h showed a tumor uptake value of 0.26+/-0.166; when rats were pretreated with DES, the value changed to 0.22+/-0.044. Priming tumor-bearing rats with estradiol, a tumor uptake value for [I-131]ITX was increased to 0.48+/-0.107 at 6 h. In the [?H]estradiol receptor assay, tumors had a mean estrogen receptor density of 7.5 fmol/mg of protein. In gamma scintigraphic imaging studies with [(131)]]ITX, the rabbit uterus uptake can be blocked by pretreatment with DES. Both iodotamoxifen and tamoxifen reduced ER(+) breast tumor growth at the dose of 50 mu g in tumor-bearing mice. The findings indicate that tamoxifen analogue uptake in tumors occurs via an ER-mediated process. Both analogues should have potential for diagnosing functioning ER(+) breast cancer.