Optimized synthesis and indium complex formation with the bifunctional chelator NODIA-Me,Organic & Biomolecular Chemistry

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Optimized synthesis and indium complex formation with the bifunctional chelator NODIA-Me
Organic & Biomolecular Chemistry ( IF 2.9 ) Pub Date : 2018-09-24 , DOI: 10.1039/c8ob01981a
Christian Weinmann _{1,

2,

3,

4,

5} , Jason P. Holland _{6,

7,

8,

9} , Tilman Läppchen _{1,

1,

2,

3,

4} , Harald Scherer _{3,

4,

5,

10} , Stephan Maus _{1,

4,

11,

12,

13} , Tobias Stemler _{1,

4,

11,

12,

13} , Hendrik Bohnenberger _{1,

4,

11,

12,

13} , Samer Ezziddin _{1,

4,

11,

12,

13} , Philipp Kurz _{3,

4,

5,

10} , Mark D. Bartholomä _{1,

1,

2,

3,

4}

Affiliation

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.

中文翻译：

使用双功能螯合剂NODIA-Me优化合成和铟络合物的形成

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），并结合了两个额外的用于金属螯合的甲基咪唑臂和一个用于生物结合的乙酸残基。最初的两步合成由于收率低和需要半制备型RP-HPLC纯化而未达到最佳效果。在这里，使用不同的保护/脱保护技术，通过两种合成途径，将NODIA-Me的制备总收率提高了2到5倍。这样，有可能（1）以克为单位制备NODIA-Me，并且（2）避免了费时的HPLC纯化。受到^{nat / 68} Ga ^3+的最新研究结果的启发，对NODIA-Me与^{nat / 111} In ³⁺的放射标记性质和复合物形成进行了初步研究。在环境温度下实现了定量放射化学收率，提供了约30 MBq nmol ^-1的摩尔活性，在95°C下可以增加到约240 MBq nmol ^-1。在室温下，pH 5.5最适合¹¹¹ In标记，但当反应温度升高时，在5.5至8.2的pH范围内也可实现定量收率。^111种复合物的体外稳定性测试在溶液和配体激发实验中发现高动力学稳定性，这是溶液中NMR研究表明形成刚性的1：1铟螯合物的结果。总而言之，新的合成路线可高收率地大规模生产BFC NODIA-Me。此外，¹¹¹在络合实验中拓宽了我们的放射性药物螯合系统的范围。

更新日期：2018-10-18

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