Radioiodinated Azide and Isothiocyanate Derivatives of Cocaine for Irreversible Labeling of Dopamine Transporters: Synthesis and Covalent Binding Studies

详细信息    查看全文

• 作者：John R. Lever ; Mu-Fa Zou ; M. Laura Parnas ; Romain A. Duval ; Sara E. Wirtz ; Joseph B. Justice ; Roxanne A. Vaughan ; and Amy Hauck Newman
• 刊名：Bioconjugate Chemistry
• 出版年：2005
• 出版时间：May 2005
• 年：2005
• 卷：16
• 期：3
• 页码：644 - 649
• 全文大小：130K
• 年卷期：v.16,no.3(May 2005)
• ISSN：1520-4812

文摘

Two novel N-substituted-3-phenyltropane alkaloids have been labeled with iodine-125 for use asirreversible probes of dopamine transporter (DAT) binding sites. One contains an iodoaryl azide moietyfor photolabeling, while the other bears an iodoaryl isothiocyanate for direct conjugation. Bothradioligands were prepared in a one-flask procedure by electrophilic radioiodination of the corresponding aniline under no-carrier-added conditions, followed either by diazotization and treatmentwith sodium azide, or by addition of thiophosgene under basic conditions. Specifically, (-)-N-[4-(3-[¹²⁵I]iodo-4-azidophenyl)butyl]-2-carbomethoxy-3-(4-chlorophenyl)tropane ([¹²⁵I]MFZ-2-24) and (-)-N-[4-(3-[¹²⁵I]iodo-4-isothiocyanophenyl)butyl]-2-carbomethoxy-3-(4-chlorophenyl)tropane ([¹²⁵I]MFZ3-37) were synthesized. Isolation by reversed-phase HPLC and solid-phase extraction gave good averageyields of [¹²⁵I]MFZ-2-24 (67%, n = 5) and [¹²⁵I]MFZ-3-37 (45%, n = 3) with high radiochemical purities(96-99%) and specific radioactivities (>2000 mCi/mol). The utility of the radioligands wasdemonstrated by their covalent linkage to rat striatal membranes, and immunoprecipitation of a singleradiolabeled band at 80 kDa corresponding to the full-length DAT.