Optimized synthesis and indium complex formation with the bifunctional chelator NODIA-Me.
Optimized synthesis and indium complex formation with the bifunctional chelator NODIA-Me.
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使用双功能螯合剂 NODIA-Me 优化合成和铟络合物形成
DOI：
10.1039/c8ob01981a
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发表时间：
2018
影响因子：
3.2
通讯作者：
Mark D.
中科院分区：
文献类型：
--
作者：
Weinmann;Christian;Holland;Jason P;Laeppchen;Tilman;Scherer;Harald;Stephan;Stemler;Tobias;Bohnenberger;Hendrik;Ezziddin;Philipp;Bartholomae;Mark D.
双功能螯合剂NODIA-Me有望用于放射性药物的开发。NODIA-Me基于大环TACN（1,4,7-三氮杂环壬烷），并包含两个额外的甲基咪唑臂用于金属螯合和一个醋酸残基用于生物偶联。由于产率低和半制备型反相高效液相色谱纯化的要求，原两步合成法并不理想。在这里，通过使用不同的保护/去保护技术的两种合成路线，制备NODIA-Me的总收率提高了2到5倍。这样可以(1)以多克为单位制备NODIA-Me，(2)避免耗时的HPLC纯化。受nat/68Ga3+的启发，对NODIA-Me与nat/111In3+的放射性标记性能和配合物形成进行了初步研究。在环境温度下获得了定量的放射化学产率，摩尔活性为~ 30 MBq nmol - 1，在95°C时可以增加到~ 240 MBq nmol - 1。在初始条件下，pH为5.5是111in标记的最佳条件，但随着反应温度的升高，pH在5.5 ~ 8.2范围内也可获得定量产率。111In配合物的体外稳定性测试显示，在血清和配体挑战实验中，111In配合物具有很高的动力学稳定性，这是溶液中核磁共振研究显示的刚性1:1铟螯合物形成的结果。综上所述，新的合成路线使BFC NODIA-Me具有高产率和规模化的特点。此外，络合实验拓宽了我们的螯合系统在放射性药物方面的应用范围。
The bifunctional chelator NODIA-Me holds promise for radiopharmaceutical development. NODIA-Me is based on the macrocycle TACN (1,4,7-triazacyclononane) and incorporates two additional methylimidazole arms for metal chelation and an acetic acid residue for bioconjugation. The original two step synthesis was less than optimal due to low yields and the requirement of semi-preparative RP-HPLC purifications. Here, the overall yield for the preparation of NODIA-Me was improved two- to five-fold via two synthetic routes using different protection/deprotection techniques. This way, it was possible (1) to prepare of NODIA-Me on multi-gram scale and (2) to avoid time-consuming HPLC purifications. Inspired by recent results with nat/68Ga3+, preliminary studies on the radiolabeling properties and complex formation of NODIA-Me with nat/111In3+ were performed. Quantitative radiochemical yields were achieved at ambient temperature providing molar activities of ∼30 MBq nmol−1, which could be increased to ∼240 MBq nmol−1 at 95 °C. At r.t., pH 5.5 was optimal for 111In-labeling, but quantitative yields were also achieved in the pH range from 5.5 to 8.2, when the reaction temperature was increased. Stability tests of 111In complexes in vitro revealed high kinetic stabilities in serum and ligand challenge experiments, which is a consequence of the formation of rigid 1 : 1 indium chelates as shown by NMR studies in solution. In summary, the new synthetic routes afford the BFC NODIA-Me in high yields and on large scale. Further, 111In complexation experiments broaden the scope of our chelating system for radiopharmaceutical applications.
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