The long and short of it:: the influence of N-carboxyethyl versus N-carboxymethyl pendant arms on in vitro and in vivo behavior of copper complexes of cross-bridged tetraamine macrocycles
The long and short of it:: the influence of N-carboxyethyl versus N-carboxymethyl pendant arms on in vitro and in vivo behavior of copper complexes of cross-bridged tetraamine macrocycles
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DOI：
10.1039/b702938a
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发表时间：
2007-01-01
影响因子：
4
通讯作者：
Rheingold, Arnold L.
中科院分区：
文献类型：
--
作者：
Heroux, Katie J.;Woodin, Katrina S.;Rheingold, Arnold L.
已经发现带有两个N-羧甲基侧臂的交联环拉胺配体（1）形成铜（II）络合物，该铜（II）络合物在最近针对64 Cu基放射性药物的研究中表现出显著改善的生物学行为。Cu-1的动力学惰性和抗还原性被认为与其增强的性能有关。为了探索悬垂臂长度对这些性能的影响，新的交联的cyclam和cyclen配体与较长的N-羧乙基悬垂臂，2和4，和它们各自的铜（II）配合物已被合成。单以及二-O-质子化形式的Cu-2也已被分离和结构表征。Cu-2和Cu-4的光谱和结构特性，它们在5 M HCl中的动力学惰性，以及电化学行为已经得到，并与它们的N-羧甲基臂同系物Cu-1和Cu-3进行了比较。只有基于环拉胺的Cu-1和Cu-2对酸解络合显示出异常高的动力学惰性。虽然这两种络合物也表现出准可逆的Cu（II）/Cu（I）还原，但Cu-2更容易还原+400 mV的实质性裕度，使其处于生理还原剂的范围内。类似地，在基于环戊二烯的络合物中，Cu-4也比Cu-3更容易还原，尽管两种还原都是不可逆的。在Sprague道利大鼠中进行Cu-64标记的2和4的生物分布研究。尽管与它们的短臂同类物具有可比的酸惰性，但两种长臂配体络合物具有较差的生物清除特性。这种较差的体内行为可能是其较高还原电位的结果。
A cross-bridged cyclam ligand bearing two N-carboxymethyl pendant arms (1) has been found to form a copper(II) complex that exhibits significantly improved biological behavior in recent research towards 64Cu-based radiopharmaceuticals. Both the kinetic inertness and resistance to reduction of Cu-1 are believed to be relevant to its enhanced performance. To explore the influence of pendant arm length on these properties, new cross-bridged cyclam and cyclen ligands with longer N-carboxyethyl pendant arms, 2 and 4, and their respective copper( II) complexes have been synthesized. Both mono- as well as di-O-protonated forms of Cu-2 have also been isolated and structurally characterized. The spectral and structural properties of Cu-2 and Cu-4, their kinetic inertness in 5 M HCl, and electrochemical behavior have been obtained and compared to those of their N-carboxymethyl-armed homologs, Cu-1 and Cu-3. Only the cyclam-based Cu-1 and Cu-2 showed unusually high kinetic inertness towards acid decomplexation. While both of these complexes also exhibited quasi-reversible Cu(II)/Cu(I) reductions, Cu-2 is easier to reduce by a substantial margin of + 400 mV, bringing it within the realm of physiological reductants. Similarly, of the cyclen-based complexes, Cu-4 is also easier to reduce than Cu-3 though both reductions are irreversible. Biodistribution studies of Cu-64-labeled 2 and 4 were performed in Sprague Dawley rats. Despite comparable acid inertness to their shorter-armed congeners, both longer-armed ligand complexes have poorer bio-clearance properties. This inferior in vivo behavior may be a consequence of their higher reduction potentials.