Generation of novel radiolabeled opiates through site-selective iodination |
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Authors: | Majumdar Susruta Burgman Maxim Haselton Nathan Grinnell Steven Ocampo Julia Pasternak Anna Rose Pasternak Gavril W |
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Institution: | a Molecular Pharmacology and Chemistry Program and Department of Neurology, Memorial Sloan-Kettering Cancer Center, 1275 York Ave., New York, NY 10065, USA b Department of Neurology and Neuroscience, Weill Cornell Medical College, New York, NY 10065, USA |
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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 (125I-BNtxA, 18), 6β-naloxamine (125I-BNalA, 19) and 6β-oxymorphamine (125I-BOxyA, 20) with specific activities of 2100 Ci/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 125I-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 125I-radioligands should prove valuable in future studies of opioid binding sites. |
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Keywords: | NHS N-hydroxy succinimide THF Tetrahydrofuran DCC Dicyclohexyl carbodiimide NH4OAc Ammonium acetate NaBH3CN Sodium cyanoborohydride MeOH Methanol rt room temperature DCM Methylene chloride DIEA N N-Diisopropyl ethyl amine n-Bu3SnCl Tributyl tin chloride BuLi Butyl lithium Na2S2O5 Sodium metabisulfite AcOH Acetic acid |
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