title: Generation of novel radiolabeled opiates through site-selective iodination.
abstract: Tritiated opioid radioligands have proven valuable in exploring opioid binding sites. However, tritium has many limitations. Its low specific activity and limited counting efficiency makes it difficult to examine low abundant, high affinity sites and its disposal is problematic due to the need to use organic scintillants and its relatively long half-life. To overcome these issues, we have synthesized both unlabeled and carrier-free radioiodinated iodobenzoyl derivatives of 6β-naltrexamine ((125)I-BNtxA, 18), 6β-naloxamine ((125)I-BNalA, 19) and 6β-oxymorphamine ((125)I-BOxyA, 20) with specific activities of 2100Ci/mmol. To optimize the utility of the radioligand, we designed a synthesis in which the radiolabel is incorporated in the last synthetic step, which required the selective iodination of the benzoyl moiety without incorporation into the phenolic A ring. Competition studies demonstrated high affinity of the unlabelled compounds for opioid receptors in transfected cell lines, as did the direct binding of the (125)I-ligands to the opioid receptors. The radioligand displayed very high sensitivity, enabling a marked reduction in tissue, as well as excellent signal/noise characteristics. These new (125)I-radioligands should prove valuable in future studies of opioid binding sites.
authors.affiliation: Molecular Pharmacology and Chemistry Program and Department of Neurology, Memorial Sloan-Kettering Cancer Center, 1275 York Ave., New York, NY 10065, USA.
authors.forename: Susruta
authors.initials: S
authors.lastname: Majumdar
authors.forename: Maxim
authors.initials: M
authors.lastname: Burgman
authors.forename: Nathan
authors.initials: N
authors.lastname: Haselton
authors.forename: Steven
authors.initials: S
authors.lastname: Grinnell
authors.forename: Julia
authors.initials: J
authors.lastname: Ocampo
authors.forename: Anna Rose
authors.initials: AR
authors.lastname: Pasternak
authors.forename: Gavril W
authors.initials: GW
authors.lastname: Pasternak
mesh_terms: D000818:Animals; D001665:Binding Sites; D001667:Binding, Competitive; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D006801:Humans; D007457:Iodine Radioisotopes; D015394:Molecular Structure; D018377:Neurotransmitter Agents / Q000138:chemical synthesis / Q000737:chemistry; D010111:Oxymorphone / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D011869:Radioligand Assay; D011957:Receptors, Opioid / Q000378:metabolism*
chemical_list: D007457:Iodine Radioisotopes; D018377:Neurotransmitter Agents; D011957:Receptors, Opioid; C036406:oxymorphamine; D010111:Oxymorphone