Bromine- and iodine-substituted 16α,17α-dioxolane progestins for breast tumor imaging and radiotherapy: Synthesis and receptor binding affinity

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 16α,17α-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 16α,17α,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 16α,17α-[(R)-1′-α-(5-bromofurylmethylidene)dioxyl] -21-hydroxy-19-norpregn-4-ene-3,20-dione (endo-6; RBA = 65 and moderate lipophilicity), 21-fluoro-16α,17α-[(R)-1′-α-(5- iodofurylmethylidene)dioxyl]-19-norpregn-4-ene-3,20-dione (endo-14; RBA = 40) and 21-fluoro-16α,17α-[(S)-1′-β-(-iodophenylmethylidene) dioxyl]-19-norpregn-4-cne-3,20-dione (exo-16; RBA = 34).