title: Preparation and evaluation of 17-ethynyl-substituted 16 alpha-[18F]fluoroestradiols: selective receptor-based PET imaging agents.
abstract: We have prepared and studied six new analogs of 16 alpha-fluoroestradiol (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 18F by the nucleophilic displacement of the corresponding 16 beta-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.
authors.affiliation: Division of Radiation Sciences, Edward Mallinckrodt Institute of Radiology, Washington University School of Medicine, St Louis, MO 63110.
authors.forename: H F
authors.initials: HF
authors.lastname: VanBrocklin
authors.forename: M G
authors.initials: MG
authors.lastname: Pomper
authors.forename: K E
authors.initials: KE
authors.lastname: Carlson
authors.forename: M J
authors.initials: MJ
authors.lastname: Welch
authors.forename: J A
authors.initials: JA
authors.lastname: Katzenellenbogen
mesh_terms: D000818:Animals; D001798:Blood Proteins / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D004958:Estradiol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism / Q000493:pharmacokinetics; D005260:Female; D005462:Fluorine Radioisotopes; D009132:Muscles / Q000378:metabolism; D011485:Protein Binding; D051381:Rats; D011919:Rats, Inbred Strains; D011960:Receptors, Estrogen / Q000032:analysis / Q000378:metabolism; D014018:Tissue Distribution; D014055:Tomography, Emission-Computed; D014599:Uterus / Q000378:metabolism
chemical_list: D001798:Blood Proteins; D002352:Carrier Proteins; D005462:Fluorine Radioisotopes; D011960:Receptors, Estrogen; D004958:Estradiol; C043436:16-fluoroestradiol; C066617:17-ethynyl-16-fluoroestradiol