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Tamoxifen is a selective estrogen receptor modulator extensively used on estrogen receptor-positive breast cancer treatment. However, clinical evidences demonstrate the increased incidence of undesirable side effects during chronic therapies, the most life threatening being uterine cancers. Some of these effects are related to tissue-dependent estrogenic actions of tamoxifen, but the exact mechanisms remain poorly understood. We have designed and synthesized a novel fluorescent tamoxifen derivative, FLTX1, and characterized its biological and pharmacological activities. Using confocal microscopy, we demonstrate that FLTX1 colocalizes with estrogen receptor α (ERα). Competition studies showed that FLTX1 binding was totally displaced by unlabeled tamoxifen and partially by estradiol, indicating the existence of non-ER-related triphenylethylene-binding sites. Ligand binding assays showed that FLTX1 exhibits similar affinity for ER than tamoxifen. FLTX1 exhibited antiestrogenic activity comparable to tamoxifen in MCF7 and T47D cells transfected with 3xERE-luciferase reporter. Interestingly, FLTX1 lacked the strong agonistic effect of tamoxifen on ERα-dependent transcriptional activity. Additionally, in vivo assays in mice revealed that unlike tamoxifen, FLTX1 was devoid of estrogenic uterotrophic effects, lacked of hyperplasic and hypertrophic effects, and failed to alter basal proliferating cell nuclear antigen immunoreactivity. In the rat uterine model of estrogenicity/antiestrogenicity, FLTX1 displayed antagonistic activity comparable to tamoxifen at lower doses, and only estrogenic uterotrophy at the highest dose. We conclude that the fluorescent derivative FLTX1 is not only a suitable probe for studies on the molecular pharmacology of tamoxifen, but also a potential therapeutic substitute to tamoxifen, endowed with potent antiestrogenic properties but devoid of uterine estrogenicity., (Copyright © 2013 Elsevier B.V. All rights reserved.)