Preparation and evaluation of 17-ethynyl-substituted 16α-[¹⁸F]fluoroestradiols: Selective receptor-based PET imaging agents

We have prepared and studied six new analogs of 16α-fluoroestradiol (FES): 17α- and 17β-ethynyl-FES (7 [FEES]and 7a), and the 11β-ethyl (8 and 8a) and 11β-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 16α position with ¹⁸F by the nucleophilic displacement of the corresponding 16β-trifluoromethanesulfonate with nBu₄N¹⁸F. Subsequent ethynylation with lithium trimethylsilylacetylide yielded the FEES analogs (total synthesis time: 120 min; effective specific activity: 200-2400 Ci/mmol). Selective uptake in the uterus was high for [¹⁸F)7, [¹⁸F]8, [¹⁸F]9 and [¹⁸F]9a (% ID/g values at 1 h: 11.2, 12.9, 9.9 and 8.3, respectively), while uptake was effectively blocked by coinjection of an excess of unlabeled estradiol. The FEES analogs, [¹⁸F]7, [¹⁸F]8 and [¹⁸F]9, exhibited the highest selectivity, in terms of target (uterus)-to-blood ratios, ever seen amongst estrogen radiopharmaceuticals, 154, 145 and 169, respectively. The analogs [¹⁸F]7a and [¹⁸F]8a displayed no uptake in the uterus, consistent with their low RBAs. Metabolism studies revealed that most of the 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 imaging of ER-rich target tissues.