Novel chelating agents for potential clinical applications of copper
Novel chelating agents for potential clinical applications of copper
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DOI：
10.1016/s0969-8051(01)00287-6
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发表时间：
2002-01-01
影响因子：
3.1
通讯作者：
Brechbiel, MW
中科院分区：
文献类型：
--
作者：
Ma, DS;Lu, F;Brechbiel, MW
铜提供了独特的放射性同位素选择。（Cu-60, Cu-61, Cu-62， Cu-64和Cu-67），半衰期从9.8 min到61.9 h，适合成像和/或放疗。在肽/抗体靶向放疗中，研究最多的铜螯合剂之一1,4,8,11-四氮杂环十四烷-1,4,8,11-四乙酸（TETA）已用于临床试验，但已注意到体内铜蓝蛋白和/或超氧化物歧化酶的转运。本研究合成了一系列以N，N',N ' -三（2-吡啶基甲基）-1,3,5-顺式，顺式，-三氨基环己烷（tachpyr）为基础的新型六齿螯合剂，并与TETA比较，评价了其铜配合物的血清稳定性。在3、4或5位修饰的tachpyr铜配合物或用咪唑取代吡啶的铜配合物具有与Cu[TETA]相当的血清稳定性。交叉激发时，Cu[TETA]与tachpyr或1,3,5-顺式，顺式三氨基环己烷-N，N',N ' -三-（2-甲基-（N-甲基咪唑））（IM）相比，tachpyr和IM表现出优于TETA的铜螯合能力。当受到大量过量的非放射性铜的挑战时，观察到铜与tachpyr放射性铜配合物的交换。因此，tachpyr、1,3,5-顺式、顺式、-三氨基环己烷-N，N′，N′-三-（3-甲基-2-甲基吡啶亚胺）（tachpyr(3- me)）、1,3,5-顺式、顺式、-三氨基环己烷-N，N′，N′-三-（4-甲基-2-甲基吡啶亚胺）（tachpyr(4-Me)）、1,3,5-顺式、顺式、-三氨基环己烷-N，N′，N′-三-（5-甲基-2-甲基吡啶亚胺）（tachpyr(5-Me)）和IM容易形成铜配合物，稳定性高。这些新型螯合剂为开发用于诊断和治疗的新型铜放射性药物提供了有吸引力的线索。(C) 2002爱思唯尔科学有限公司版权所有。
Copper offers a unique selection of radioisotopes. (Cu-60, Cu-61, Cu-62, Cu-64, and Cu-67) with half-lives ranging from 9.8 min to 61.9 h suitable for imaging and/or radiotherapy. In peptide/antibody targeted radiotherapy one of the most studied chelating agents for copper, 1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid (TETA), has been employed in clinical trials, but transchelation to ceruloplasmin and/or superoxide dismutase in vivo has been noted. In this study, a series of novel hexadentate chelating agents based on N,N',N"-tris(2-pyridylmethyl)-1,3,5-cis,cis,-triaminocyclohexane (tachpyr) have been synthesized and the serum stability of their copper complexes was evaluated as compared to TETA. Copper complexes of tachpyr modified at the 3, 4, or 5 position or with replacement of pyridine by imidazole have serum stability comparable to Cu[TETA]. When the complexes were cross-challenged, Cu[TETA] versus tachpyr or 1,3,5-cis,cis-triaminocyclohexane-N,N',N"-tris-(2-methyl-(N-methylimidazole)) (IM), tachpyr and IM appear to have superior copper chelation ability to TETA. When challenged by a large excess of non-radioactive copper, copper exchange with the tachpyr radio-copper complex was observed. However, tachpyr clearly exhibited a significant preference for Cu(II) over Zn(II) or Fe(III), Therefore, tachpyr, 1,3,5-cis,cis,-triaminocyclohexane-N,N',N"-tri-(3-methyl-2-methylpyridineimine) (tachpyr(3-Me)), 1,3,5-cis,cis,-triaminocyclohexane-N,N',N"-tri-(4-methyl-2-methylpyridineimine) (tachpyr(4-Me)), 1,3,5-cis,cis,-triaminocyclohexane-N,N',N"-tri-(5-methyl-2-methylpyridineimine) (tachpyr(5-Me)) and IM easily form copper complexes with high stability. These novel chelating agents provide an attractive lead for creation of new copper radiopharmaceuticals for diagnosis and therapy applications. (C) 2002 Elsevier Science Inc. All rights reserved.