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

  • Xiaozhu Wang
    Xiaozhu Wang
    Medicinal Inorganic Chemistry Group, Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, British Columbia V6T 1Z1, Canada
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  • , 
  • María de Guadalupe Jaraquemada-Peláez
    María de Guadalupe Jaraquemada-Peláez
    Medicinal Inorganic Chemistry Group, Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, British Columbia V6T 1Z1, Canada
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    Orcidhttp://orcid.org/0000-0002-6204-707X
  • , 
  • Cristina Rodríguez-Rodríguez
    Cristina Rodríguez-Rodríguez
    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
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    Orcidhttp://orcid.org/0000-0002-3313-4422
  • , 
  • Yang Cao
    Yang Cao
    Medicinal Inorganic Chemistry Group, Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, British Columbia V6T 1Z1, Canada
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    Orcidhttp://orcid.org/0000-0001-8636-7919
  • , 
  • Christian Buchwalder
    Christian Buchwalder
    Faculty of Pharmaceutical Sciences, University of British Columbia, 2405 Wesbrook Mall, Vancouver, British Columbia V6T 1Z3, Canada
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    Orcidhttp://orcid.org/0000-0001-5577-8870
  • , 
  • Neha Choudhary
    Neha Choudhary
    Medicinal Inorganic Chemistry Group, Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, British Columbia V6T 1Z1, Canada
    Life Sciences Division, TRIUMF, 4004 Wesbrook Mall, Vancouver, British Columbia V6T 2A3, Canada
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  • , 
  • Una Jermilova
    Una Jermilova
    Medicinal Inorganic Chemistry Group, Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, British Columbia V6T 1Z1, Canada
    Life Sciences Division, TRIUMF, 4004 Wesbrook Mall, Vancouver, British Columbia V6T 2A3, Canada
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  • , 
  • Caterina F. Ramogida
    Caterina F. Ramogida
    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
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  • , 
  • Katayoun Saatchi
    Katayoun Saatchi
    Faculty of Pharmaceutical Sciences, University of British Columbia, 2405 Wesbrook Mall, Vancouver, British Columbia V6T 1Z3, Canada
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  • , 
  • Urs O. Häfeli
    Urs O. Häfeli
    Faculty of Pharmaceutical Sciences, University of British Columbia, 2405 Wesbrook Mall, Vancouver, British Columbia V6T 1Z3, Canada
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  • , 
  • Brian O. Patrick
    Brian O. Patrick
    Medicinal Inorganic Chemistry Group, Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, British Columbia V6T 1Z1, Canada
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  • , and 
  • Chris Orvig*
    Chris Orvig
    Medicinal Inorganic Chemistry Group, Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, British Columbia V6T 1Z1, Canada
    *[email protected]
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    Orcidhttp://orcid.org/0000-0002-2830-5493
Cite this: J. Am. Chem. Soc. 2018, 140, 45, 15487–15500
Publication Date (Web):October 16, 2018
https://doi.org/10.1021/jacs.8b09964
Copyright © 2018 American Chemical Society
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    Abstract

    Abstract Image

    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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    The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/jacs.8b09964.

    • Protonation constants of H4octox, representative spectra of the in batch UV spectrophotometric titration of 3.06 × 10–5 M H2O solution of H4octox, representative spectra of the simultaneous UV–potentiometric titration of 9.55 × 10–4 M solution of H4octox, speciation plots of H4octox calculated using protonation constants in Table 3, representative spectra of the UV–potentiometric titration of the Y3+–H4octox system, representative spectra of the UV–potentiometric titration of the La3+–H4octox system, representative spectra of the UV–potentiometric titration of the Gd3+–H4octox system, representative spectra of the UV–potentiometric titration of the Lu3+–H4octox system, representative spectra of the in batch UV spectrophotometric titration of the In3+–H4octox system, [Y(octox)]− complex stability challenge against 5 equiv of Fe3+, [In(octox)]− complex stability challenge against 5 equiv of Fe3+, 1H NMR spectrum of compound 2 in CD2Cl2, 13C NMR spectrum of compound 2 in CD2Cl2, 1H NMR spectrum of H4octox (3) in D2O, 13C NMR spectrum of H4octox (3) in D2O, 1H NMR spectrum of Na[In(octox)] in D2O, 2D NOESY spectrum of Na[In(octox)] in D2O, ORTEP diagram of the [La3(octox)4]7–·6H2O, crystallographic data for the La-octox structure, DFT-optimized structures and MEP mappings of isomers of [In(octox)]− and [In(octapa)]− (PDF)

    • Dynamic SPECT/CT animated images of maximum intensity projections (top view) (MPG)

    • Dynamic SPECT/CT animated images of maximum intensity projections (3D view) (MPG)

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