Synthesis and evaluation of highly selective quinazoline-2,4-dione ligands for sphingosine-1-phosphate receptor 2.
Synthesis and evaluation of highly selective quinazoline-2,4-dione ligands for sphingosine-1-phosphate receptor 2.
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1-磷酸鞘氨醇受体 2 的高选择性喹唑啉-2,4-二酮配体的合成和评价。
DOI：
10.1039/d1md00357g
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发表时间：
2022
影响因子：
4.1
通讯作者：
Tu,Zhude
中科院分区：
文献类型：
--
作者：
Luo,Zonghua;Liu,Hui;Yu,Yanbo;Gropler,RobertJ;Klein,RobynS;Tu,Zhude
合成了29个新的喹唑啉-2,4-二酮类化合物，并采用[32P]S1P结合试验测定了它们与鞘氨醇-1-磷酸受体2 （S1PR2）结合的IC50值。7个化合物2a、2g、2h、2i、2j、2k和5h表现出较高的S1PR2结合能力（IC50值< 50 nM），其中4个新化合物2g、2i、2j和2k的IC50值（<10 nM）分别为6.3、5.7、4.8和2.6 nM，与S1PR1、3、4和5相比，S1PR2对S1PR2具有较高的选择性。化合物2a和2i通过前体13和2k的O-[11C]甲基化进行C-11放射性合成，具有良好的放射化学产率（35-40%），高化学和放射化学纯度（>98%）和高摩尔活性（轰击结束时为153-222 GBq μmol−1）。[11C]2a和[11C]2i进一步通过体外生物分布研究进行评价。结果表明，这两种示踪剂的脑摄取都很低，阻碍了它们在神经影像学应用的潜力。这类S1PR2 PET示踪剂在外周组织疾病中的进一步探索正在进行中。
A series of twenty-nine new quinazoline-2,4-dione compounds were synthesized and their IC50 values for binding toward sphingosine-1-phosphate receptor 2 (S1PR2) were determined using a [32P]S1P binding assay. Seven compounds 2a, 2g, 2h, 2i, 2j, 2k, and 5h exhibit high S1PR2 binding potencies (IC50 values < 50 nM) and four of these new compounds 2g, 2i, 2j, and 2k have IC50 values (<10 nM) of 6.3, 5.7, 4.8, and 2.6 nM, and are highly selective for S1PR2 over other S1PR subtypes, S1PR1, 3, 4, and 5. Compounds 2a and 2i were chosen for C-11 radiosynthesis through O-[11C]methylation of precursors 13 and 2k with good radiochemical yields (35–40%), high chemical and radiochemical purity (>98%), and high molar activity (153–222 GBq μmol−1, at the end of bombardment). [11C]2a and [11C]2i were further evaluated by the ex vivo biodistribution study. The results showed that both tracers have low brain uptake, preventing their potential for neuroimaging application. Further explorations of this class of S1PR2 PET tracers in peripheral tissue diseases are underway.