H4octapa: An Acyclic Chelator for 111In Radiopharmaceuticals

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• 作者：Eric W. Price ; Jacqueline F. Cawthray ; Gwendolyn A. Bailey ; Cara L. Ferreira ; Eszter Boros ; Michael J. Adam ; Chris Orvig
• 刊名：The Journal of the American Chemical Society
• 出版年：2012
• 出版时间：May 23, 2012
• 年：2012
• 卷：134
• 期：20
• 页码：8670-8683
• 全文大小：555K
• 年卷期：v.134,no.20(May 23, 2012)
• ISSN：1520-5126

文摘

This preliminary investigation of the octadentate acyclic chelator H₄octapa (N₄O₄) with ¹¹¹In/¹¹⁵In³⁺ has demonstrated it to be an improvement on the shortcomings of the current industry 鈥済old standards鈥?DOTA (N₄O₄) and DTPA (N₃O₅). The ability of H₄octapa to radiolabel quantitatively ¹¹¹InCl₃ at ambient temperature in 10 min with specific activities as high as 2.3 mCi/nmol (97.5% radiochemical yield) is presented. In vitro mouse serum stability assays have demonstrated the ¹¹¹In complex of H₄octapa to have improved stability when compared to DOTA and DTPA over 24 h. Mouse biodistribution studies have shown that the radiometal complex [¹¹¹In(octapa)]^{鈭?/sup> has exceptionally high in vivo stability over 24 h with improved clearance and stability compared to [111In(DOTA)]鈭?/sup>, demonstrated by lower uptake in the kidneys, liver, and spleen at 24 h. 1H/13C NMR studies of the [In(octapa)]鈭?/sup> complex revealed a 7-coordinate solution structure, which forms a single isomer and exhibits no observable fluxional behavior at ambient temperature, an improvement to the multiple isomers formed by [In(DTPA)]2鈥?/sup> and [In(DOTA)]鈭?/sup> under the same conditions. Potentiometric titrations have determined the thermodynamic formation constant of the [In(octapa)]鈭?/sup> complex to be log K_ML = 26.8(1). Through the same set of analyses, the [111/115In(decapa)]2鈥?/sup> complex was found to have nonoptimal stability, with H₅decapa (N₅O₅) being more suitable for larger metal ions due to its higher potential denticity (e.g., lanthanides and actinides). Our initial investigations have revealed the acyclic chelator H₄octapa to be a valuable alternative to the macrocycle DOTA for use with 111In, and a significant improvement to the acyclic chelator DTPA.}