What a Difference a Carbon Makes: H4octapa vs H4C3octapa, Ligands for In-111 and Lu-177 Radiochemistry

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• 作者：Eric W. Price ; Brian M. Zeglis ; Jacqueline F. Cawthray ; Jason S. Lewis ; Michael J. Adam ; Chris Orvig
• 刊名：Inorganic Chemistry
• 出版年：2014
• 出版时间：October 6, 2014
• 年：2014
• 卷：53
• 期：19
• 页码：10412-10431
• 全文大小：913K
• ISSN：1520-510X

文摘

The acyclic ligands H₄C3octapa and p-SCN-Bn-H₄C3octapa were synthesized for the first time, using nosyl protection chemistry. These new ligands were compared to the previously studied ligands H₄octapa and p-SCN-Bn-H₄octapa to determine the extent to which the addition of a single carbon atom to the backbone of the ligand would affect metal coordination, complex stability, and, ultimately, utility for in vivo radiopharmaceutical applications. Although only a single carbon atom was added to H₄C3octapa and the metal donor atoms and denticity were not changed, the solution chemistry and radiochemistry properties were drastically altered, highlighting the importance of careful ligand design and radiometal鈥搇igand matching. It was found that [In(C3octapa)]^{鈭?/sup> and [Lu(C3octapa)]鈭?/sup> were substantially different from the analogous H₄octapa complexes, exhibiting fluxional isomerization and a higher number of isomers, as observed by 1H NMR, VT-NMR, and 2D COSY/HSQC-NMR experiments. Past evaluation of the DFT structures of [In(octapa)]鈭?/sup> and [Lu(octapa)]鈭?/sup> revealed very symmetric complexes; in contrast, the [In(C3octapa)]鈭?/sup> and [Lu(C3octapa)]鈭?/sup> complexes were much less symmetric, suggesting lower symmetry and less rigidity than that of the analogous H₄octapa complexes. Potentiometric titrations revealed the formation constants (log K_ML, pM) were 鈭? units lower for the In3+ and Lu3+ complexes of H₄C3octapa when compared to that of the more favorable H₄octapa ligand (鈭? orders of magnitude less thermodynamically stable). The bifunctional ligands p-SCN-Bn-H₄C3octapa and p-SCN-Bn-H₄octapa were conjugated to the antibody trastuzumab and radiolabeled with 111In and 177Lu. Over a 5 day stability challenge experiment in blood serum, 111In-octapa鈥?and 111In-C3octapa鈥搕rastuzumab immunoconjugates were determined to be 鈭?1 and 鈭?4% stable, respectively, and 177Lu-octapa鈥?and 177Lu-C3octapa鈥搕rastuzumab, 鈭?9% and 鈭?% stable, respectively. This work suggests that 5-membered chelate rings are superior to 6-membered chelate rings for large metal ions like In3+ and Lu3+, which is a crucial consideration for the design of bifunctional chelates for bioconjugation to targeting vectors for in vivo work.}