title: Synthesis of novel arylpyrazolo corticosteroids as potential ligands for imaging brain glucocorticoid receptors.
abstract: Corticosteroids regulate a variety of essential physiological functions, such as mineral balance and stress. The great interest in these steroids, especially the glucocorticoids, stems from roles they are thought to play in neuropsychiatric disorders, such as severe depression and anxiety.The development of glucocorticoid receptor (GR) ligands which are appropriately labeled with short-lived positron-emitting radioisotopes would allow the non-invasive in-vivo imaging and mapping of brain GRs by means of positron emission tomography (PET). In this context we have synthesized a series of novel arylpyrazolo steroids exhibiting different substitution patterns at the D-ring of the steroid skeleton, as ligands for brain GRs. Special attention was given to 4-fluorophenyl pyrazolo steroids, which are known to display high binding affinity toward the GR. The compounds were evaluated in a competitive radiometric receptor binding assay to determine their relative binding affinities (RBA) to the GR. Some compounds show good binding affinities of up to 56% in comparison to dexamethasone (100%). In initial experiments, selected candidates were labeled with the positron emitter fluorine-18 and in one case with the gamma-emitter iodine-131.
authors.affiliation: Institut für Bioanorganische und Radiopharmazeutische Chemie, FZ-Rossendorf e.V., Postfach 510119, Dresden 01314, Germany. wuest@fz-rossendorf.de
authors.forename: Frank
authors.initials: F
authors.lastname: Wüst
authors.forename: Kathryn E
authors.initials: KE
authors.lastname: Carlson
authors.forename: John A
authors.initials: JA
authors.lastname: Katzenellenbogen
mesh_terms: D000305:Adrenal Cortex Hormones / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism*; D001667:Binding, Competitive; D001921:Brain / Q000378:metabolism*; D005462:Fluorine Radioisotopes; D008024:Ligands; D015394:Molecular Structure; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism*; D011965:Receptors, Glucocorticoid / Q000032:analysis / Q000378:metabolism*; D014055:Tomography, Emission-Computed
chemical_list: D000305:Adrenal Cortex Hormones; D005462:Fluorine Radioisotopes; D008024:Ligands; D011720:Pyrazoles; D011965:Receptors, Glucocorticoid