Synthesis of a potent and selective 18F-Labeled δ-opioid receptor antagonist derived from the Dmt-Tic pharmacophore for positron emission tomography imaging
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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DOI：
10.1021/jm7014765
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发表时间：
2008-03-27
影响因子：
7.3
通讯作者：
Chen, Xiaoyuan
中科院分区：
文献类型：
--
作者：
Ryu, Eun Kyoung;Wu, Zhanhong;Chen, Xiaoyuan
本文报道了从DMT-Tic药效团中提取的两种新的选择性β-阿片受体拮抗剂的鉴定和药理学特征，它们在正电子发射断层扫描(PET)成像中具有潜在的应用价值。基于其高的三角洲选择性，H-DMT-Tic-epsilon-Lys(Z)-OH(参比化合物1)是合成N-琥珀酰亚胺4-[(18)F]氟苯甲酸酯([(18)F]SFB)与Boc-DMT-Tic-epsilon-Lys(Z)-OH在37℃微碱性条件下反应15min，用TFA脱保护，并进行高效液相色谱纯化得到的(18)F标记化合物的一个有用的起点。[(18)F]-1的总合成时间为120分钟，从[(18)F]SFB(n=5)开始衰变校正的放化产率约为25-30%(n=5)，有效比活度约为46GBq/mMol。体外放射自显影研究显示[(18)F]-1在纹状体和皮质中显著摄取，并被1和选择性d-阿片受体拮抗剂UFP-501显著阻断，表明[(18)F]-1与β-阿片受体具有高度的特异性结合。非侵入性的microPET成像研究显示，[18F]-1在大鼠脑中缺失，因为它无法通过血脑屏障。本研究证实了[(18)F]-1用于外周阿片受体成像的适宜性。
Identification and pharmacological characterization of two new selective delta-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 delta selectivity, H-Dmt-Tic-epsilon-Lys(Z)-OH (reference compound 1) is a useful starting point for the synthesis of (18)F-labeled compounds prepared by the coupling of N-succinimidyl 4-[(18)F]fluorobenzoate ([(18)F]SFB) with Boc-Dmt-Tic-epsilon-Lys(Z)-OH tinder slightly basic conditions at 37 degrees C for 15 min, deprotection with TFA, and HPLC purification. The total synthesis time was 120 min, and the decay-corrected radiochemical yield of [(18)F]-1 was about 25-30% (n = 5) starting from [(18)F]SFB (n = 5) with an effective specific activity about 46 GBq/mu mol. In vitro autoradiography studies showed prominent uptake of [(18)F]-1 in the striatum and cortex with significant blocking by 1 and UFP-501 (selective d-opioid receptor antagonist), suggesting high specific binding of [(18)F]-1 to delta-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 [(18)F]-1 for imaging peripheral delta-opioid receptors.