H 4octapa: An acyclic chelator for 111In radiopharmaceuticals

Eric W. Price, Jacqueline F. Cawthray, Gwendolyn A. Bailey, Cara L. Ferreira, Eszter Boros, Michael J. Adam, Chris Orvig

Research output: Contribution to journalArticlepeer-review

90 Scopus citations


This preliminary investigation of the octadentate acyclic chelator H 4octapa (N 4O 4) with 111In/ 115In 3+ has demonstrated it to be an improvement on the shortcomings of the current industry "gold standards" DOTA (N 4O 4) and DTPA (N 3O 5). The ability of H 4octapa to radiolabel quantitatively 111InCl 3 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 H 4octapa to have improved stability when compared to DOTA and DTPA over 24 h. Mouse biodistribution studies have shown that the radiometal complex [ 111In(octapa)] - has exceptionally high in vivo stability over 24 h with improved clearance and stability compared to [ 111In(DOTA)] -, demonstrated by lower uptake in the kidneys, liver, and spleen at 24 h. 1H/ 13C NMR studies of the [In(octapa)] - 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- and [In(DOTA)] - under the same conditions. Potentiometric titrations have determined the thermodynamic formation constant of the [In(octapa)] - complex to be log K ML = 26.8(1). Through the same set of analyses, the [ 111/115In(decapa)] 2- complex was found to have nonoptimal stability, with H 5decapa (N 5O 5) 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 H 4octapa to be a valuable alternative to the macrocycle DOTA for use with 111In, and a significant improvement to the acyclic chelator DTPA.

Original languageEnglish (US)
Pages (from-to)8670-8683
Number of pages14
JournalJournal of the American Chemical Society
Issue number20
StatePublished - May 23 2012
Externally publishedYes


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