title: Imaging progesterone receptor in breast tumors: synthesis and receptor binding affinity of fluoroalkyl-substituted analogues of tanaproget.
abstract: The progesterone receptor (PR) is estrogen regulated, and PR levels in breast tumors can be used to predict the success of endocrine therapies targeting the estrogen receptor (ER). Tanaproget is a nonsteroidal progestin agonist with very high PR binding affinity and excellent in vivo potency. When appropriately radiolabeled, it might be used to image PR-positive breast tumors noninvasively by positron emission tomography (PET). We describe the synthesis and PR binding affinities of a series of fluoroalkyl-substituted 6-aryl-1,4-dihydrobenzo[d][1,3]oxazine-2-thiones, analogues of Tanaproget. Some of these compounds have subnanomolar binding affinities, higher than that of either Tanaproget itself or the high affinity PR ligand R5020. Structure-binding affinity relationships can be rationalized by molecular modeling of ligand complexes with PR, and the enantioselectivity of binding has been predicted. These compounds are being further evaluated as potential diagnostic PET imaging agents for breast cancer, and enantiomerically pure materials of defined stereochemistry are being prepared.
authors.affiliation: Department of Chemistry, University of Illinois, 600 South Mathews Avenue, Urbana, Illinois 61801, USA.
authors.forename: Hai-Bing
authors.initials: HB
authors.lastname: Zhou
authors.forename: Jae Hak
authors.initials: JH
authors.lastname: Lee
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Mayne
authors.forename: Kathryn E
authors.initials: KE
authors.lastname: Carlson
authors.forename: John A
authors.initials: JA
authors.lastname: Katzenellenbogen
mesh_terms: D000818:Animals; D048588:Benzoxazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D001667:Binding, Competitive; D001943:Breast Neoplasms / Q000378:metabolism*; D005260:Female; D005461:Fluorine; D005462:Fluorine Radioisotopes; D008958:Models, Molecular; D011397:Promegestone / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D011980:Receptors, Progesterone / Q000378:metabolism*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D013871:Thiones / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism
chemical_list: D048588:Benzoxazines; D005462:Fluorine Radioisotopes; D011980:Receptors, Progesterone; D013871:Thiones; D005461:Fluorine; D011397:Promegestone; C504446:tanaproget