Novel bimodal bifunctional ligands for radioimmunotherapy and targeted MRI
Novel bimodal bifunctional ligands for radioimmunotherapy and targeted MRI
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DOI：
10.1021/bc800050x
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发表时间：
2008-07-01
影响因子：
4.7
通讯作者：
Brechbiel, Martin W.
中科院分区：
文献类型：
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作者：
Chong, Hyun-Soon;Song, Hyun A.;Brechbiel, Martin W.
制备了结构新颖的双功能配体C-NETA和C-NE 3 TA，它们各自具有无环和大环部分，并作为放射免疫治疗（RIT）和靶向磁共振成像（MRI）的潜在螯合物进行了评价。七齿C-NE 3 TA是在C-NETA的制备过程中偶然发现的。建立了C-NETA和C-NE 3 TA的优化合成方法，包括极性和拖尾反应中间体叔丁基C-NETA（2）和叔丁基C-NE 3 TA（3）的半制备型HPLC纯化。制备C-NETA和C-NE 3 TA的新Gd（III）络合物作为用于靶向MRI的对比增强剂。T-1弛豫率数据表明Gd（C-NETA）和Gd（C-NE 3 TA）具有比Gd（C-DOTA）更高的弛豫率，Gd（C-DOTA）是市售MRI造影剂的双功能形式; Gd（DOTA）。用Lu-177、Y-90、Pb-203、Bi-205/6和Gd-153放射性标记C-NETA和C-NE 3 TA;并在人血清中评估放射性标记的相应复合物的体外稳定性。体外研究表明，所评价的放射性标记的复合物在血清中稳定11天，但C-NETA和C-NE 3 TA的Ph-203复合物除外，其在血清中解离。进一步评价了C-NETA和C-NE 3 TA放射性标记的Lu-177、Y-90或Gd-153复合物在无胸腺小鼠中的体内稳定性，并具有优异或可接受的体内生物分布特征。Bi-205/6-C-NE 3 TA在正常器官中表现出极快速的血液清除和低放射性水平，而Bi-205/6-C-NETA在血液和所有器官中表现出低放射性水平，但肾脏除外，在肾脏中观察到相对较高的肾放射性摄取。进一步修饰C-NETA和C-NE 3 TA以与单克隆抗体曲妥珠单抗缀合。
The structurally novel bifunctional ligands C-NETA and C-NE3TA, each possessing both acyclic and macrocyclic moieties, were prepared and evaluated as potential chelates for radioimmunotherapy (RIT) and targeted magnetic resonance imaging (MRI). Heptadentate C-NE3TA was fortuitously discovered during the preparation of C-NETA. An optimized synthetic method to C-NETA and C-NE3TA including purification of the polar and tailing reaction intermediates, tert-butyl C-NETA (2) and tert-butyl C-NE3TA (3) using semiprep HPLC was developed. The new Gd(III) complexes of C-NETA and C-NE3TA were prepared as contrast enhancement agents for use in targeted MRI. The T-1 relaxivity data indicate that Gd(C-NETA) and Gd(C-NE3TA) possess higher relaxivity than Gd(C-DOTA), a bifunctional version of a commercially available MRI contrast agent; Gd(DOTA). C-NETA and C-NE3TA were radiolabeled with Lu-177, Y-90, Pb-203, Bi-205/6, and Gd-153; and in vitro stability of the radiolabeled corresponding complexes was assessed in human serum. The in vitro studies indicate that the evaluated radiolabeled complexes were stable in serum for I I days with the exception being the Ph-203 complexes of C-NETA and C-NE3TA, which dissociated in serum. C-NETA and C-NE3TA radiolabeled Lu-177, Y-90, or Gd-153 complexes were further evaluated for in vivo stability in athymic mice and possess excellent or acceptable in vivo biodistribution profile. Bi-205/6-C-NE3TA exhibited extremely rapid blood clearance and low radioactivity level at the normal organs, while Bi-205/6-C-NETA displayed low radioactivity level in the blood and all of the organs except for the kidney where relatively high renal uptake of radioactivity is observed. C-NETA and C-NE3TA were further modified for conjugation to the monoclonal antibody Trastuzumab.