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Purpose: To investigate whether longitudinal functional PET imaging of mammary tumors using the radiopharmaceuticals [18F]FDG (to measure glucose uptake), [18F]FES [to measure estrogen receptor (ER) levels], or [18F]FFNP [to measure progesterone receptor (PgR) levels] is predictive of response to estrogen-deprivation therapy. Experimental Design: [18F]FDG, [18F]FES, and [18F]FFNP uptake in endocrine-sensitive and -resistant mammary tumors was quantified serially by PET before ovariectomy or estrogen withdrawal in mice, and on days 3 and 4 after estrogen-deprivation therapy. Specificity of [18F]FFNP uptake in ERα+ mammary tumors was determined by competition assay using unlabeled ligands for PgR or glucocorticoid receptor (GR). PgR expression was also assayed by immunohistochemistry (IHC). Results: The levels of [18F]FES and [18F]FDG tumor uptake remained unchanged in endocrine-sensitive tumors after estrogen-deprivation therapy compared with those at pretreatment. In contrast, estrogen-deprivation therapy led to a reduction in PgR expression and [18F]FFNP uptake in endocrine-sensitive tumors, but not in endocrine-resistant tumors, as early as 3 days after treatment; the changes in PgR levels were confirmed by IHC. Unlabeled PgR ligand R5020 but not GR ligand dexamethasone blocked [18F]FFNP tumor uptake, indicating that [18F]FFNP bound specifically to PgR. Therefore, a reduction in FFNP tumor to muscle ratio in mammary tumors predicts sensitivity to estrogen-deprivation therapy. Conclusions: Monitoring the acute changes in ERα activity by measuring [18F]FFNP uptake in mammary tumors predicts tumor response to estrogen-deprivation therapy. Longitudinal noninvasive PET imaging using [18F]FFNP is a robust and effective approach to predict tumor responsiveness to endocrine treatment. Clin Cancer Res; 21(5); 1063–70. ©2014 AACR.