PREPARATION AND EVALUATION OF 17-ETHYNYL-SUBSTITUTED 16-ALPHA-[F-18]FLUOROESTRADIOLS - SELECTIVE RECEPTOR-BASED PET IMAGING AGENTS

We have prepared and studied six new analogs of 16-alpha-fluoroestradi ol (FES): 17-alpha- and 17-beta-ethynyl-FES (7 [FEES] and 7a), and the 11-beta-ethyl (8 and 8a) and 11-beta-methoxy (9 and 9a) derivatives, novel estrogen receptor-based PET imaging agents. The relative binding affinity (RBA) for the estrogen receptor (ER) versus FES is increased for 7, 9 and 9a but decreased for 7a, 8 and 8a. All six analogs have been labeled in the 16-alpha position with F-18 by the nucleophilic di splacement of the corresponding 16-beta-trifluoromethane-sulfonate wit h (nBu4NF)-F-18. Subsequent ethynylation with lithium trimethylsilylac etylide yielded the FEES analogs (total synthesis time: 120 min; effec tive specific activity: 200-2400 Ci/mmol). Selective uptake in the ute rus was high for [F-18]7, [F-18]8, [F-18]9 and [F-18]9a (% ID/g values at 1 h: 11.2, 12.9, 9.9 and 8.3, respectively), while uptake was effe ctively blocked by coinjection of an excess of unlabeled estradiol. Th e FEES analogs, [F-18]7, [F-18]8 and [F-18]9, exhibited the highest se lectivity, in terms of target (uterus)-to-blood ratios, ever seen amon gst estrogen radiopharmaceuticals, 154, 145 and 169, respectively. The analogs [F-18]7a and [F-18]8a displayed no uptake in the uterus, cons istent with their low RBAs. Metabolism studies revealed that most of t he uterine activity is unmetabolized while the blood exhibits a rapid and subsequently sustained mixture of metabolites. The muscle shows a metabolic profile intermediate to the uterus and blood. These analogs provide an array of desirable characteristics for the optimal PET imag ing of ER-rich target tissues.