Arylamides hybrids of two high-affinity σ2 receptor ligands as tools for the development of PET radiotracers
Arylamides hybrids of two high-affinity σ2 receptor ligands as tools for the development of PET radiotracers
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DOI：
10.1016/j.ejmech.2011.05.057
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发表时间：
2011-09-01
影响因子：
6.7
通讯作者：
Berardi, Francesco
中科院分区：
文献类型：
--
作者：
Abate, Carmen;Ferorelli, Savina;Berardi, Francesco
1-环己基-4-[3-（5-甲氧基-1，2，3，4-四氢萘-1-基）丙基]哌嗪1（PB 28）和2-甲氧基-5-甲基-N-[4-（6，7-二甲氧基-3，4-二氢-1H-异喹啉-2-基）丁基]苯甲酰胺2（RHM-1）代表肿瘤诊断的先导物，因为它们对σ（2）受体具有高亲和力。为了获得用于sigma（2）PET示踪剂开发的良好候选物，设计了1和2之间的杂化结构。当6，7-二甲氧基四氢异喹啉与邻甲氧基取代的芳基酰胺（11 a，12 a，15 a）连接时，达到优异的σ（1）/σ（2）选择性。并且对于这些苯甲酰胺，假设在σ位点的活性构象中存在分子内氢键。然而，这些优异的σ（2）配体伴随着与P-gp的相互作用。当肿瘤过度表达P-gp时，这可能限制它们作为σ（2）受体PET剂的用途。P-gp相互作用仅为中等的化合物15 a代表了用于开发可用于过表达P-gp的肿瘤的σ（2）PET示踪剂的有趣工具。(C)2011年Elsevier Masson SAS。All rights reserved.
1-Cyclohexy1-4-[3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)propyl]piperazine 1 (PB28) and 2-Methoxy-5-methyl-N-[4-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)butyl]benzamide 2 (RHM-1) represent leads for tumor diagnosis, given their high affinity at sigma(2) receptors. With the purpose of obtaining good candidates for sigma(2) PET tracers development, hybrid structures between 1 and 2 were designed. Excellent sigma(1)/sigma(2) selectivities were reached when 6,7-dimethoxytetrahydroisoquinoline was linked to an o-methoxy substituted arylamide (11a, 12a, 15a). and for these benzamides an intramolecular H-bond in the active conformation at the sigma sites, was hypothesized. However these excellent sigma(2) ligands were accompanied by interaction with P-gp. which may limit their use as sigma(2) receptor PET agents when tumors overexpress P-gp. Compound 15a whose P-gp interaction was just moderate represents an interesting tool for the development of sigma(2) PET tracers useful in tumors overexpressing P-gp. (C) 2011 Elsevier Masson SAS. All rights reserved.