title: New iodinated progestins as potential ligands for progesterone receptor imaging in breast cancer. Part 1: Synthesis and in vitro pharmacological characterization.
abstract: Five putative iodinated progesterone receptor (PR) binding ligands were synthesized and evaluated as potential imaging agents for PR-positive human breast tumours. Two compounds (E- and Z-17-hydroxy-21-iodo-19-nor-17alpha-pregna-4,20-dien-3-one; E- and Z-IPG1) were previously described, but are re-evaluated. The other three were novel compounds: two nortestosterone analogues derived from ORG 3236 (E- and Z-13-ethyl-17-hydroxy-21-iodo-11-methylene-18,19-dinor-17alpha-pre gna-4,20-diene-3-one; E- and Z-IPG2) and one norprogesterone analogue derived from ORG 2058 (21-[4-iodophenoxy]-16alpha-ethyl-19-norpregn-4-ene-3, 20-dione; IPG3). The E-iodovinyl nortestosterone compounds were obtained by a new route of synthesis. Competitive binding studies were performed to determine their binding affinities for the PR in three types of tissue (human MCF-7 breast tumour cells and rat uterine and mammary tumour tissue) and for the androgen receptor (AR) in human MCF-7 breast tumour cells, as well as for the sex hormone-binding globulin (SHBG) and corticosteroid-binding globulin (CBG) in human plasma. All four 17alpha-iodovinyl nortestosterone derivatives displayed high binding affinity for the human PR, that of Z-IPG1 and E- and Z-IPG2 being even higher than that of ORG2058. Their affinities for the rat PR were somewhat lower, especially those of both E-isomers. The affinity of IPG3 was lower for both the human and rat PR. The nortestosterone derivatives also showed AR binding, the relative binding affinities ranging from 4.3 to 17.0% as compared with 5alphaDHT. Additionally, neither of these steroids displayed any significant binding to either SHBG or CBG in human plasma. We conclude that the in vitro binding properties of all four 17alpha-iodovinyl nortestosterone derivatives warrant evaluation of the distribution characteristics of their 123I-labelled analogues to determine their usefulness as PR imaging agents.
authors.affiliation: Amersham Cygne and Laboratory of Organic Chemistry, Eindhoven University of Technology, The Netherlands. tgtojb@chem.tue.nl
authors.forename: J C
authors.initials: JC
authors.lastname: van den Bos
authors.forename: L J
authors.initials: LJ
authors.lastname: Rijks
authors.forename: P A
authors.initials: PA
authors.lastname: van Doremalen
authors.forename: K
authors.initials: K
authors.lastname: de Bruin
authors.forename: A G
authors.initials: AG
authors.lastname: Janssen
authors.forename: E A
authors.initials: EA
authors.lastname: van Royen
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000000981:diagnostic imaging* / Q000378:metabolism; D002850:Chromatography, Gel; D005260:Female; D006801:Humans; D007457:Iodine Radioisotopes; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D009277:Nandrolone / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism; D045167:Progesterone Congeners / Q000138:chemical synthesis / Q000378:metabolism*; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000378:metabolism*; D051381:Rats; D011980:Receptors, Progesterone / Q000378:metabolism*; D015899:Tomography, Emission-Computed, Single-Photon; D014407:Tumor Cells, Cultured
chemical_list: D007457:Iodine Radioisotopes; D008024:Ligands; D045167:Progesterone Congeners; D019275:Radiopharmaceuticals; D011980:Receptors, Progesterone; D009277:Nandrolone