Synthesis and biological evaluation of [125I]- and [123I]-4-iododexetimide, a potent muscarinic cholinergic receptor antagonist.
Synthesis and biological evaluation of [125I]- and [123I]-4-iododexetimide, a potent muscarinic cholinergic receptor antagonist.
复制标题
[125I]-和[123I]-4-碘右乙亚胺（一种有效的毒蕈碱胆碱能受体拮抗剂）的合成和生物学评价。
DOI：
10.1021/jm00125a021
复制
发表时间：
1989
影响因子：
7.3
通讯作者：
WagnerJr,HN
中科院分区：
文献类型：
--
作者：
Wilson,AA;Dannals,RF;Ravert,HT;Frost,JJ;WagnerJr,HN
合成了一系列右替米特的卤代外消旋类似物(1)，并测定了它们与M胆碱能受体的亲和力。其中一个类似物4-碘代二酰亚胺(21)被125I和123I有效地标记，具有较高的比活性。体外结合研究和体内生物分布研究表明，~(123)I标记的21可能有助于用单光子发射计算机断层扫描对活体人脑中的M胆碱能受体进行成像。最近人们对M-AChR成像的兴趣主要是由于在一些神经退行性疾病中观察到m-AChR的区域分布的变化。1目前，只有~(123)I标记的4-碘奎宁基苯甲酸酯(4-IQNB)被用作高比活度放射性示踪剂，用于单光子发射计算机断层扫描(SPECT)在人体研究中对m-AChR的无创性显像。2酸诱导三氮烯分解法制备的4-IQNB的产率较低(18%)。4鉴于目前SPECT质量123I的成本(30美元/mci)，更高的产量是经济上可行的广泛临床试验所必需的。本工作的目的是设计一种高亲和力、高选择性的m-AChR拮抗剂，可以高产率、高比活性地快速标记~(123)I。地塞米特(Dexetimide((S)-(+)-3-phenyl-3-[(l-phenyl-methyl)-4-piperidinyl]-2，6-piperidinedione)(1)是一种已知的
A series of halogenated racemic analogues of dexetimide (1) was synthesized and their affinity for the muscarinic cholinergic receptor measured. One analogue, 4-iododexetimide (21), was efficiently labeled with 125I and 123I at high specific activity. Invitro binding studies and in vivo biodistribution studies suggest that 123I-labeled 21 may be useful for imaging muscarinic cholinergic receptors in the living human brain with single photon emission computed tomography.Much of the recent interest in imaging muscarinic cholinergic receptors (m-AChR) has been prompted by observations of changes in the regional distribution of m-AChR in some neurodegenerative disorders as measured by postmortem assay. 1 At present only 4-iodo-quinuclidinyl benzylate (4-IQNB), labeled with 123I, has been used as a high specific activity radiotracer for the noninvasive imaging of m-AChR in human studies by single photon emission computed tomography (SPECT). 2 However, the yield of 4-IQNB, prepared by the acid-in-duced triazene decomposition method, 3 is relatively low (18%). 4 Given the current cost of SPECT quality 123I (> $30/mCi), higheryields are necessary for extensive clinical trials to be economically feasible. The objective of the present work was to design a high-affinity, selective m-AChR antagonist which could be rapidly labeled with 123I in high yield and at high specific activity. Dexetimide ((S)-(+)-3-phenyl-3-[(l-phenyl-methyl)-4-piperidinyl]-2, 6-piperidinedione)(1) is a known