We have evaluated 6 alpha-[18F]fluoroprogesterone as a potential imaging agent for progesterone receptor (PgR)-positive breast cancer. 6 alpha-Fluoroprogesterone (1) was obtained via halofluorination of the C-5 double bond in pregnenolone, followed by oxidation of the 3 beta-OH group, elimination of HBr from C-4,5, and epimerization at the C-6 center. The relative binding affinity (RBA) of 6 alpha-fluoroprogesterone (1) to PgR is 11 (R5020 = 100), and its binding selectivity index (BSI, i.e. the ratio of the RBA to the non-specific binding, NSB) is 14.4; these values are similar to those of progesterone. 17 alpha-Acetoxy-6 alpha-fluoroprogesterone (2) was also prepared by the same method, but was not used for fluorine-18 labeling studies because its binding affinity for PgR is very low (0.9). The synthesis of 1 was adapted to fluorine-18 labeling and although the overall radiochemical yield was low (decay-corrected, 0.3%), progestin [18F]1 was obtained in moderately high effective specific activity (147 Ci/mmol). In vivo distribution studies using estrogen-primed immature female rats showed that 6 alpha-fluoroprogesterone ([18F]1) has low uterine uptake, low target tissue selectivity, and high fat uptake, presumably due to its low RBA and BSI. High uptake in bone, which indicates extensive metabolic defluorination, suggests that the C-6 position of steroids may not be a good site for fluorine-18 labeling.