title: Synthesis and evaluation of [123I]labelled analogues of the partial inverse agonist Ro 15-4513 for the study of diazepam-insensitive benzodiazepine receptors.
abstract: The imidazobenzodiazepines ethyl 8-iodo-5,6 dihydro-5-methyl-6-oxo-4H-imidazo[1,5a][1,4] benzodiazepine-3-carboxylate 1 and tert-butyl 8-iodo-5,6 dihydro-5-methyl-6-oxo-4H-imidazo [1,5a][1,4] benzodiazepine-3-carboxylate 2 were prepared to study the diazepam-insensitive (DI) benzodiazepine receptor (BZR) subtype. The [123I] analogues were prepared via iododestannylation reactions in radiochemical yields of 70-80% and a specific activity >2,500 Ci/mmol. The tert-butyl analogue [123I]-2 exhibited nanomolar affinity for BZRs in homogenate membranes of rat cerebellum with Kd values for the diazepam-sensitive (DS) and DI receptors of 3.18 +/- 0.58 and 13.55 +/- 2.72 nM, respectively. The Bmax for cerebellar DS and DI receptors were 1,276 +/- 195 and 518 +/- 26 fmol/mg protein, respectively.
authors.affiliation: Radiopharmaceutical Division R&D, Australian Nuclear Science and Technology Organisation, NSW, Sydney. akx@ansto.gov.au
authors.forename: A
authors.initials: A
authors.lastname: Katsifis
authors.forename: K
authors.initials: K
authors.lastname: Mardon
authors.forename: M
authors.initials: M
authors.lastname: McPhee
authors.forename: F
authors.initials: F
authors.lastname: Mattner
authors.forename: B
authors.initials: B
authors.lastname: Dikic
authors.forename: D
authors.initials: D
authors.lastname: Ridley
mesh_terms: D000818:Animals; D001345:Autoradiography; D001386:Azides / Q000493:pharmacokinetics*; D001569:Benzodiazepines / Q000138:chemical synthesis* / Q000493:pharmacokinetics*; D001921:Brain / Q000378:metabolism*; D003975:Diazepam / Q000494:pharmacology*; D005260:Female; D007202:Indicators and Reagents; D007457:Iodine Radioisotopes / Q000493:pharmacokinetics*; D015394:Molecular Structure; D011869:Radioligand Assay; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D051381:Rats; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000032:analysis* / Q000187:drug effects / Q000378:metabolism; D013329:Structure-Activity Relationship; D014018:Tissue Distribution
chemical_list: D001386:Azides; D007202:Indicators and Reagents; D007457:Iodine Radioisotopes; D019275:Radiopharmaceuticals; D011963:Receptors, GABA-A; D001569:Benzodiazepines; C042957:Ro 15-4513; D003975:Diazepam