title: Bromine- and iodine-substituted 16alpha,17alpha-dioxolane progestins for breast tumor imaging and radiotherapy: synthesis and receptor binding affinity.
abstract: Progesterone receptors (PRs) are present in many breast tumors, and their levels are increased by certain endocrine therapies. We describe the synthesis and PR binding affinities of a series of bromine- and iodine-substituted 16alpha,17alpha-dioxolane progestins, some of which, when appropriately radiolabeled, are potential agents for diagnostic imaging of PR-positive breast tumors using positron emission tomography (PET) and for radiotherapy. These compounds were synthesized from halogenated furanyl, phenyl, and thiophenyl aldehydes and a progestin 16alpha,17alpha,21-triol (5) in the presence of HClO4 or Sc(OTf)3 in high yields under optimized conditions. A new reagent, perfluoro-1-butanesulfonyl fluoride (PBSF), was used to convert the C-21 OH to F in high yields. The relative binding affinities (RBAs) of the most promising compounds for the PR (RBA of R5020 = 100) were 16alpha,17alpha-[(R)-1'-alpha-(5-bromofurylmethylidene)dioxyl]-21-hydroxy-19-norpregn-4-ene-3,20-dione (endo-6; RBA = 65 and moderate lipophilicity), 21-fluoro-16alpha,17alpha-[(R)-1'-alpha-(5-iodofurylmethylidene)dioxyl]-19-norpregn-4-ene-3,20-dione (endo-14; RBA = 40) and 21-fluoro-16alpha,17alpha-[(S)-1'-beta-(4-iodophenylmethylidene)dioxyl]-19-norpregn-4-ene-3,20-dione (exo-16; RBA = 34).
authors.affiliation: Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
authors.forename: Dong
authors.initials: D
authors.lastname: Zhou
authors.forename: Kathryn E
authors.initials: KE
authors.lastname: Carlson
authors.forename: John A
authors.initials: JA
authors.lastname: Katzenellenbogen
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Welch
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D001943:Breast Neoplasms / Q000000981:diagnostic imaging* / Q000532:radiotherapy*; D004148:Dioxolanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D005260:Female; D009376:Neoplasms, Hormone-Dependent / Q000000981:diagnostic imaging / Q000532:radiotherapy; D009652:Norpregnenes / Q000138:chemical synthesis* / Q000737:chemistry; D011372:Progestins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D011877:Radionuclide Imaging; D051381:Rats; D011980:Receptors, Progesterone / Q000737:chemistry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: C513007:16,17-(1'-alpha-(5-bromofurylmethylidene)dioxyl)-21-hydroxy-19-norpregn-4-ene-3,20-dione; C513009:21-fluoro-16,17-(1'-alpha-(4-iodofurylmethylidene)dioxyl)-21-hydroxy-19-norpregn-4-ene-3,20-dione; C513008:21-fluoro-16,17-(1'-alpha-(5-iodofurylmethylidene)dioxyl)-19-norpregn-4-ene-3,20-dione; D004148:Dioxolanes; D009652:Norpregnenes; D011372:Progestins; D011980:Receptors, Progesterone; C097314:progesterone receptor B