Synthesis of a Potent and Selective 18F-Labeled δ-Opioid Receptor Antagonist Derived from the Dmt-Tic Pharmacophore for Positron Emission Tomography Imaging

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• 作者：Eun Kyoung Ryu ; Zhanhong Wu ; Kai Chen ; Lawrence H. Lazarus ; Ewa ; D. Marczak ; Yusuke Sasaki ; Akihiro Ambo ; Severo Salvadori ; Chuancheng Ren ; Heng Zhao ; Gianfranco Balboni ; Xiaoyuan Chen
• 刊名：Journal of Medicinal Chemistry
• 出版年：2008
• 出版时间：March 27, 2008
• 年：2008
• 卷：51
• 期：6
• 页码：1817 - 1823
• 全文大小：270K
• 年卷期：v.51,no.6(March 27, 2008)
• ISSN：1520-4804

文摘

Identification and pharmacological characterization of two new selective δ-opioid receptor antagonists, derived from the Dmt-Tic pharmacophore, of potential utility in positron emission tomography (PET) imaging are described. On the basis of its high δ selectivity, H-Dmt-Tic-ε-Lys(Z)-OH (reference compound 1) is a useful starting point for the synthesis of ¹⁸F-labeled compounds prepared by the coupling of N-succinimidyl 4-[¹⁸F]fluorobenzoate ([¹⁸F]SFB) with Boc-Dmt-Tic-ε-Lys(Z)-OH under slightly basic conditions at 37 °C for 15 min, deprotection with TFA, and HPLC purification. The total synthesis time was 120 min, and the decay-corrected radiochemical yield of [¹⁸F]-1 was about 25–30% (n = 5) starting from [¹⁸F]SFB (n = 5) with an effective specific activity about 46 GBq/µmol. In vitro autoradiography studies showed prominent uptake of [¹⁸F]-1 in the striatum and cortex with significant blocking by 1 and UFP-501 (selective δ-opioid receptor antagonist), suggesting high specific binding of [¹⁸F]-1 to δ-opioid receptors. Noninvasive microPET imaging studies revealed the absence of [¹⁸F]-1 in rat brain, since it fails to cross the blood−brain barrier. This study demonstrates the suitability of [¹⁸F]-1 for imaging peripheral δ-opioid receptors.