Dipartimento Farmacochimico, Università degli Studi di Bari ALDO MORO, Via Orabona 4, I-70125 Bari, Italy.
Eur J Med Chem. 2011 Sep;46(9):4733-41. doi: 10.1016/j.ejmech.2011.05.057. Epub 2011 May 30.
1-Cyclohexyl-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 σ(2) receptors. With the purpose of obtaining good candidates for σ(2) PET tracers development, hybrid structures between 1 and 2 were designed. Excellent σ(1)/σ(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 σ sites, was hypothesized. However these excellent σ(2) ligands were accompanied by interaction with P-gp, which may limit their use as σ(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 σ(2) PET tracers useful in tumors overexpressing P-gp.
1-环己基-4-[3-(5-甲氧基-1,2,3,4-四氢萘-1-基)丙基]哌嗪 1（PB28）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）因其在 σ(2)受体上的高亲和力而成为肿瘤诊断的先导化合物。为了获得用于 σ(2) PET 示踪剂开发的良好候选物，设计了 1 和 2 之间的杂合结构。当 6,7-二甲氧基四氢异喹啉与邻甲氧基取代的芳酰胺连接时，达到了优异的 σ(1)/σ(2)选择性（11a、12a、15a），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-糖蛋白的相互作用，当肿瘤过度表达 P-糖蛋白时，这可能限制它们作为 σ(2)受体 PET 剂的使用。化合物 15a 与 P-糖蛋白的相互作用只是中等程度，代表了用于开发在过度表达 P-糖蛋白的肿瘤中有用的 σ(2) PET 示踪剂的有趣工具。
