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J Am Chem Soc. 2018 Nov 14;140(45):15487-15500. doi: 10.1021/jacs.8b09964. Epub 2018 Nov 5.

H4octox: Versatile Bimodal Octadentate Acyclic Chelating Ligand for Medicinal Inorganic Chemistry.

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Medicinal Inorganic Chemistry Group, Department of Chemistry , University of British Columbia , 2036 Main Mall , Vancouver , British Columbia V6T 1Z1 , Canada.
Center for Comparative Medicine , 4145 Wesbrook Mall , Vancouver , British Columbia V6T 1W5 , Canada.
Department of Physics and Astronomy , University of British Columbia , 6224 Agronomy Road , Vancouver , British Columbia V6T 1Z1 , Canada.
Faculty of Pharmaceutical Sciences , University of British Columbia , 2405 Wesbrook Mall , Vancouver , British Columbia V6T 1Z3 , Canada.
Life Sciences Division , TRIUMF , 4004 Wesbrook Mall , Vancouver , British Columbia V6T 2A3 , Canada.
Department of Chemistry , Simon Fraser University , 8888 University Drive , Burnaby , British Columbia V5A 1S6 , Canada.


H4octox, a versatile new octadentate acyclic chelating ligand, has been investigated as an alternative to the acyclic DTPA and the macrocyclic DOTA for trivalent metal ions useful in diagnostic medical imaging or therapeutic applications (Y3+, In3+, La3+, Gd3+, Lu3+). The synthesis of H4octox is straightforward in less steps and thus more economical than those of most previously reported chelators. Complex formation equilibria in the presence of Y3+, In3+, La3+, Gd3+, and Lu3+ revealed fast chelation and high metal-sequestering capacity. Quantitative labeling with 111In3+ was achieved within 15 min at room temperature at ligand concentrations as low as 10-7 M, exactly the properties required for the development of kit-based radiopharmaceuticals. In vitro serum stability studies and in vivo SPECT imaging confirmed excellent complex stability of [111In(octox)]-. Moreover, it is more lipophilic than most of the multidentate carboxylate- or picolinate-based chelators; it therefore shows more liver clearance and provides a complementary choice in the design of metal-based pharmaceuticals and in the tuning of their pharmacokinetic properties. Finally, H4octox showed a large fluorescence enhancement upon complexation with different metals, in particular, with Y3+ and Lu3+, which could be useful for non-radioactive fluorescent stability and cell studies as well as bimodal imaging. Excellent in vitro stability of [Y(octox)]- against transferrin and Fe3+ was confirmed employing this fluorescence.


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