Copper-64 radiolabeling and biological evaluation of bifunctional chelators for radiopharmaceutical development
Copper-64 radiolabeling and biological evaluation of bifunctional chelators for radiopharmaceutical development
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DOI：
10.1016/j.nucmedbio.2012.05.009
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发表时间：
2012-11-01
影响因子：
3.1
通讯作者：
Rogers, Buck E.
中科院分区：
文献类型：
--
作者：
De Silva, Ravindra A.;Jain, Sandeep;Rogers, Buck E.
简介：近年来，开发新型双功能螯合物将铜-64连接到生物分子上一直是一个活跃的研究领域。然而，这些Cu-64-螯合物中的许多具有差的体内稳定性或苛刻的放射性标记条件。C-NE3TA（4-羧甲基-7-[2-（羧甲基氨基）-3-（三氟甲基）苯基]氨基）-N-甲基-N-（2-（三氟甲基）苯基）-N-甲基-N-（三氟甲基）-（4-硝基-苯基）-丙基]-[1，4，7]三唑-楠-1-基-乙酸）和N-NE 3 TA（4-羧甲基-7-[2-羧甲基-（4-硝基-苄基）-氨基]-乙基-[1，4，7]三唑烷-1-基-乙酸）在室温下与Cu-64的标记效率进行了评价，并在体外和体内进行了评价。体外研究包括使用分光光度法和大鼠血清稳定性与Cu（II）的络合动力学，而体内生物分布使用SOD小鼠进行评估。C-NE 3 TA和N-NE 3 TA几乎立即与Cu（II）形成络合物，C-NE 3 TA与Cu（II）的络合比Cu（II）-N-NE 3 TA的形成快。在大鼠血清中孵育48 h后，Cu-64-N-NE 3 TA和Cu-64-C-NE 3 TA的完整性分别为96.1%和90.5%。这与对照螯合剂p-NH 2-Bn-DOTA和p-NH 2-Bn-NOTA的Cu-64络合物相比，Cu-64在络合物中的保留率分别为93.9%和97.9%。Cu-64-N-NE 3 TA和Cu-64-C-NE 3 TA的体内评价表明从除肝脏以外的正常组织中的良好清除，其中与Cu-64-N-NE 3 TA和Cu-64-C-NE 3 TA的1小时相比，在24小时分别保留59%和51%的放射性。这与Cu-64-p-NH 2-Bn-DOTA和Cu-64-p-NH 2-Bn-NOTA的78%和3%保留率相比。结论：这些研究表明，虽然N-NE 3 TA和C-NE 3 TA似乎是比p-NH 2-Bn-DOTA上级的Cu-64螯合剂，但它们并不比p-NH 2-Bn-NOTA好。然而，在与生物分子缀合后评估这些螯合剂可能仍然是有趣的。(C)2012 Elsevier Inc. All rights reserved.
Introduction: The development of novel bifunctional chelates for attaching copper-64 to biomolecules has been an active area of research for several years. However, many of these Cu-64-chelates have poor in vivo stability or harsh radiolabeling conditions.Methods: In this study, two triazacyclononane analogs: C-NE3TA (4-carboxymethyl-7-[2-(carboxymethylamino)-3-(4-nitro-phenyl)-propy]-[1,4,7]triazo-nan-1-yl-acetic acid) and N-NE3TA (4-carboxymethyl-7-[2-carboxymethyl-(4-nitro-benzyl)-amino]-ethyl-[1,4,7]triazonan-1-yl-acetic acid) were evaluated for their labeling efficiency with Cu-64 at room temperature and evaluated in vitro and in vivo. In vitro studies included complexation kinetics with Cu(II) using a spectrophotometric method and rat serum stability, while the in vivo biodistribution was evaluated using SOD mice.Results: C-NE3TA and N-NE3TA were labeled at >95% efficiency up to similar to 3.4 Ci/mu mol. Both C-NE3TA and N-NE3TA formed complexes with Cu(II) almost immediately, with the Cu(II) complexation by C-NE3TA being faster than the formation of Cu(II)-N-NE3TA. Both Cu-64-N-NE3TA and Cu-64-C-NE3TA were 96.1% and 90.5% intact after 48 h incubation in rat serum, respectively. This is compared to Cu-64 complexes of the control chelators, p-NH2-Bn-DOTA and p-NH2-Bn-NOTA, with 93.9% and 97.9% retention of Cu-64 in the complex, respectively. In vivo evaluation of Cu-64-N-NE3TA and Cu-64-C-NE3TA demonstrates good clearance from normal tissues except for the liver, where 59% and 51% of the radioactivity is retained at 24 h compared to 1 h for Cu-64-N-NE3TA and Cu-64-C-NE3TA, respectively. This compares to 78% and 3% retention for Cu-64-p-NH2-Bn-DOTA and Cu-64-p-NH2-Bn-NOTA.Conclusions: These studies demonstrate that While N-NE3TA and C-NE3TA appear to be superior chelators for Cu-64 than p-NH2-Bn-DOTA, they are not better than p-NH2-Bn-NOTA. Nevertheless, it may still be interesting to evaluate these chelators after conjugation to biomolecules. (C) 2012 Elsevier Inc. All rights reserved.