I-Labeled []-2-[4-(1,2-diphenyl-1-di-butenyl)-phenoxy]-,-dimethylethanamine

Tamoxifen ([]-2-[4-(1,2-diphenyl-1-di-butenyl)-phenoxy]-,-dimethylethanamine (TAM)) is the first selective estrogen receptor (ER) modulator with extensive investigation for its anticancer properties (1, 2). The I-labeled form of TAM (I-TAM) was developed to study the tumor response to antiestrogenic treatment and the ER expression in tumors and critical normal tissues (3). TAM as first approved by the United States Food and Drug Administration in the 1970s for use in breast cancer treatment. Currently, it is widely used for the treatment of both early and advanced ER-positive breast cancer, as well as for the prevention of breast cancer in high-risk women (1, 4, 5). TAM itself is a prodrug, having relatively little affinity to ER. It is metabolized in the liver, mainly by the CYP2D6 and CYP3A4 enzymes (5, 6). Active metabolites such as 4-hydroxytamoxifen and N-desmethyl-4-hydroxytamoxifen have 30–100 times more affinity with the ER than TAM itself. These metabolites compete with estrogen for binding to ER and form a nuclear complex that inhibits DNA synthesis and blocks estrogen effects (5, 6). As a result, tumor cells stop proliferating and remain in the G and G phases of the cell cycle. In combination with other therapeutic agents or alone, TAM has also been shown to be antiangiogenic, which is, at least in part, independent of its ER-antagonist properties (7). TAM also has a number of other beneficial properties. For example, TAM lowers low-density lipoprotein cholesterol levels, increases bone density in postmenopausal women, and is effective against infertility in women with anovulatory disorders. In men, TAM is used to treat breast cancer, and it is also used to treat gynecomastia that arises from anti-androgen treatment in patients with prostate cancer. TAM has some side effects. It blocks the estrogen effects on mammary epithelial cells, but it mimics the estrogen actions in other tissues (2). The result of such selective effects on the uterus is stimulated proliferation of the endometrium (8). Each year, the risk of developing endometrial cancer is ~2‰ in women taking TAM compared with ~1‰ in women taking placebo (9). TAM also slightly increases the risk of developing uterine sarcoma. The other side effects include blood clots, strokes, cataracts, and symptoms of menopause. To maintain the beneficial properties without sharing the potentially harmful effects of TAM, a number of derivatives have been developed (2). However, these derivatives demonstrate differing amounts of success. Their ability to inhibit cancer ranges widely. Studies of tissue-based pharmacokinetics of TAM and its derivatives provide direct concentration-effect relationships in tumors and critical normal tissues, thus providing a more rational basis for the evaluation of new compounds and tumor response to treatment (10, 11). Generally speaking, the study results are controversial. Imaging studies have shown that [F]fluorotamoxifen is useful in predicting the effect of TAM therapy in patients with ER-positive breast cancer (12, 13). The I-trans-Z-iodomethyl-,-diethyltamoxifen has also been shown to be preferentially taken up by ER-positive tumors in patients with untreated primary breast cancer (14, 15). On the contrary, studies have failed to show the suitability for tumor localization of some derivatives, such as I- and Tc-labeled geometrical isomers ( and ) of the aminotamoxifen, I-idoxifene and C-toremifene (16-19). Recently, Muftuler et al. produced I-TAM and investigated its biodistribution in rats. Their study demonstrated that the biodistribution of I-TAM is ER-specific (3).