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Title: Chiral DOTA chelators as an improved platform for biomedical imaging and therapy applications

Abstract

Despite established clinical utilisation, there is an increasing need for safer, more inert gadolinium-based contrast agents, and for chelators that react rapidly with radiometals. Here we report the syntheses of a series of chiral DOTA chelators and their corresponding metal complexes and reveal properties that transcend the parent DOTA compound. We incorporated symmetrical chiral substituents around the tetraaza ring, imparting enhanced rigidity to the DOTA cavity, enabling control over the range of stereoisomers of the lanthanide complexes. The Gd chiral DOTA complexes are shown to be orders of magnitude more inert to Gd release than [GdDOTA]¯. These compounds also exhibit very-fast water exchange rates in an optimal range for high field imaging. Radiolabeling studies with (Cu-64/Lu-177) also demonstrate faster labelling properties. These chiral DOTA chelators are alternative general platforms for the development of stable, high relaxivity contrast agents, and for radiometal complexes used for imaging and/or therapy.

Authors:
 [1];  [2];  [1];  [3]; ORCiD logo [3]; ORCiD logo [2];  [2];  [1]; ORCiD logo [3];  [2]; ORCiD logo [1]
  1. The Hong Kong Polytechnic Univ., Hong Kong (China)
  2. Massachusetts General Hospital and Harvard Medical School, Charlestown, MA (United States)
  3. Univ. of Pittsburgh, Pittsburgh, PA (United States)
Publication Date:
Research Org.:
Univ. of Pittsburgh, Pittsburgh, PA (United States)
Sponsoring Org.:
USDOE Office of Science (SC)
OSTI Identifier:
1511482
Grant/Contract Number:  
SC0008833
Resource Type:
Accepted Manuscript
Journal Name:
Nature Communications
Additional Journal Information:
Journal Volume: 9; Journal Issue: 1; Journal ID: ISSN 2041-1723
Publisher:
Nature Publishing Group
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES

Citation Formats

Dai, Lixiong, Jones, Chloe M., Chan, Wesley Ting Kwok, Pham, Tiffany A., Ling, Xiaoxi, Gale, Eric M., Rotile, Nicholas J., Tai, William Chi-Shing, Anderson, Carolyn J., Caravan, Peter, and Law, Ga -Lai. Chiral DOTA chelators as an improved platform for biomedical imaging and therapy applications. United States: N. p., 2018. Web. doi:10.1038/s41467-018-03315-8.
Dai, Lixiong, Jones, Chloe M., Chan, Wesley Ting Kwok, Pham, Tiffany A., Ling, Xiaoxi, Gale, Eric M., Rotile, Nicholas J., Tai, William Chi-Shing, Anderson, Carolyn J., Caravan, Peter, & Law, Ga -Lai. Chiral DOTA chelators as an improved platform for biomedical imaging and therapy applications. United States. doi:10.1038/s41467-018-03315-8.
Dai, Lixiong, Jones, Chloe M., Chan, Wesley Ting Kwok, Pham, Tiffany A., Ling, Xiaoxi, Gale, Eric M., Rotile, Nicholas J., Tai, William Chi-Shing, Anderson, Carolyn J., Caravan, Peter, and Law, Ga -Lai. Tue . "Chiral DOTA chelators as an improved platform for biomedical imaging and therapy applications". United States. doi:10.1038/s41467-018-03315-8. https://www.osti.gov/servlets/purl/1511482.
@article{osti_1511482,
title = {Chiral DOTA chelators as an improved platform for biomedical imaging and therapy applications},
author = {Dai, Lixiong and Jones, Chloe M. and Chan, Wesley Ting Kwok and Pham, Tiffany A. and Ling, Xiaoxi and Gale, Eric M. and Rotile, Nicholas J. and Tai, William Chi-Shing and Anderson, Carolyn J. and Caravan, Peter and Law, Ga -Lai},
abstractNote = {Despite established clinical utilisation, there is an increasing need for safer, more inert gadolinium-based contrast agents, and for chelators that react rapidly with radiometals. Here we report the syntheses of a series of chiral DOTA chelators and their corresponding metal complexes and reveal properties that transcend the parent DOTA compound. We incorporated symmetrical chiral substituents around the tetraaza ring, imparting enhanced rigidity to the DOTA cavity, enabling control over the range of stereoisomers of the lanthanide complexes. The Gd chiral DOTA complexes are shown to be orders of magnitude more inert to Gd release than [GdDOTA]¯. These compounds also exhibit very-fast water exchange rates in an optimal range for high field imaging. Radiolabeling studies with (Cu-64/Lu-177) also demonstrate faster labelling properties. These chiral DOTA chelators are alternative general platforms for the development of stable, high relaxivity contrast agents, and for radiometal complexes used for imaging and/or therapy.},
doi = {10.1038/s41467-018-03315-8},
journal = {Nature Communications},
number = 1,
volume = 9,
place = {United States},
year = {2018},
month = {2}
}

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Figures / Tables:

Fig. 1 Fig. 1 : Synthetic procedures of chiral DOTA complexes. The chiral cyclens were synthesised from chiral aziridines followed by the incorporation of protected acetate arms and subsequent deprotections to give the final ligands. (a) TsOH/EtOH, RT (1a); (b) BF3·Et2O/Benzene, reflux (1b – 1d), 24 h; (c) TsOH/ACN, RT (1b, 1e);more » (d) Pd(OH)2/C, ammonium formate, trifluoroethanol, 50–75 °C, 16 h; (e) tert-butyl 2-bromoacetate, K2CO3, dry acetonitrile, 50–60 °C, 16 h; (f) TFA/DCM (1:1), 16 h; (g) 1 M HCl (L2 – L4); (h) LnCl3·6H2O, pH 7.0, 80 °C, 12 h (Ln= Eu(III), Yb(III) and Gd(III)), note for clarity the counterions are not depicted« less

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    Works referencing / citing this record:

    Towards the Rational Design of Magnetic Resonance Imaging Contrast Agents: Isolation of the Two Coordination Isomers of Lanthanide DOTA-Type Complexes
    journal, December 2003

    • Woods, Mark; Kovacs, Zoltan; Zhang, Shanrong
    • Angewandte Chemie International Edition, Vol. 42, Issue 47
    • DOI: 10.1002/anie.200352234

    Multilocus Binding Increases the Relaxivity of Protein-Bound MRI Contrast Agents
    journal, October 2005

    • Zhang, Zhaoda; Greenfield, Matthew T.; Spiller, Marga
    • Angewandte Chemie International Edition, Vol. 44, Issue 41
    • DOI: 10.1002/anie.200502245

    Monovalent and Bivalent Fibrin-specific MRI Contrast Agents for Detection of Thrombus
    journal, June 2008

    • Nair, Shrikumar A.; Kolodziej, Andrew F.; Bhole, Gandhali
    • Angewandte Chemie International Edition, Vol. 47, Issue 26
    • DOI: 10.1002/anie.200800563

    Heteroditopic Binding of Magnetic Resonance Contrast Agents for Increased Relaxivity
    journal, February 2011

    • Zhang, Zhaoda; Kolodziej, Andrew F.; Greenfield, Matthew T.
    • Angewandte Chemie International Edition, Vol. 50, Issue 11
    • DOI: 10.1002/anie.201007689

    Increasing the Chemical-Shift Dispersion of Unstructured Proteins with a Covalent Lanthanide Shift Reagent
    journal, October 2016

    • Göbl, Christoph; Resch, Moritz; Strickland, Madeleine
    • Angewandte Chemie International Edition, Vol. 55, Issue 47
    • DOI: 10.1002/anie.201607261

    Comparative study of the physicochemical properties of six clinical low molecular weight gadolinium contrast agents
    journal, January 2006

    • Laurent, Sophie; Elst, Luce Vander; Muller, Robert N.
    • Contrast Media & Molecular Imaging, Vol. 1, Issue 3
    • DOI: 10.1002/cmmi.100

    Influence of molecular parameters and increasing magnetic field strength on relaxivity of gadolinium- and manganese-based T 1 contrast agents
    journal, March 2009

    • Caravan, Peter; Farrar, Christian T.; Frullano, Luca
    • Contrast Media & Molecular Imaging, Vol. 4, Issue 2
    • DOI: 10.1002/cmmi.267

    Biodistribution of gadolinium-based contrast agents, including gadolinium deposition
    journal, December 2009

    • Aime, Silvio; Caravan, Peter
    • Journal of Magnetic Resonance Imaging, Vol. 30, Issue 6
    • DOI: 10.1002/jmri.21969

    Differences in gadolinium retention after repeated injections of macrocyclic MR contrast agents to rats: Differences in Gd Retention Between cGBCAs
    journal, July 2017

    • Bussi, Simona; Coppo, Alessandra; Botteron, Catherine
    • Journal of Magnetic Resonance Imaging, Vol. 47, Issue 3
    • DOI: 10.1002/jmri.25822

    Gadolinium-based contrast agent toxicity: a review of known and proposed mechanisms
    journal, April 2016


    The importance of water exchange rates in the design of responsive agents for MRI
    journal, April 2013


    Determination of free gadolinium(3+) as a cyclohexanediaminetetraacetic acid complex by reversed-phase HPLC in ionic gadolinium(III) chelates
    journal, January 1994

    • Kumar, Krishan.; Sukumaran, K. V.; Tweedle, M. F.
    • Analytical Chemistry, Vol. 66, Issue 2
    • DOI: 10.1021/ac00074a018

    New Class of Bright and Highly Stable Chiral Cyclen Europium Complexes for Circularly Polarized Luminescence Applications
    journal, August 2016


    In-Cell Protein Structures from 2D NMR Experiments
    journal, June 2016

    • Müntener, Thomas; Häussinger, Daniel; Selenko, Philipp
    • The Journal of Physical Chemistry Letters, Vol. 7, Issue 14
    • DOI: 10.1021/acs.jpclett.6b01074

    Synergistic Effect of Human Serum Albumin and Fullerene on Gd-DO3A for Tumor-Targeting Imaging
    journal, April 2016

    • Zhang, Ying; Zou, Toujun; Guan, Mirong
    • ACS Applied Materials & Interfaces, Vol. 8, Issue 18
    • DOI: 10.1021/acsami.5b12848

    Isomerism in Benzyl-DOTA Derived Bifunctional Chelators: Implications for Molecular Imaging
    journal, January 2015

    • Payne, Katherine M.; Woods, Mark
    • Bioconjugate Chemistry, Vol. 26, Issue 2
    • DOI: 10.1021/bc500593h

    Coordinating Radiometals of Copper, Gallium, Indium, Yttrium, and Zirconium for PET and SPECT Imaging of Disease
    journal, May 2010

    • Wadas, Thaddeus J.; Wong, Edward H.; Weisman, Gary R.
    • Chemical Reviews, Vol. 110, Issue 5
    • DOI: 10.1021/cr900325h

    Gadolinium(III) Chelates as MRI Contrast Agents:  Structure, Dynamics, and Applications
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    • Caravan, Peter; Ellison, Jeffrey J.; McMurry, Thomas J.
    • Chemical Reviews, Vol. 99, Issue 9
    • DOI: 10.1021/cr980440x

    Solution and Solid-State Characterization of Highly Rigid, Eight-Coordinate Lanthanide(III) Complexes of a Macrocyclic Tetrabenzylphosphinate
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    • Aime, Silvio; Batsanov, Andrei S.; Botta, Mauro
    • Inorganic Chemistry, Vol. 33, Issue 21
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    Polymethylated DOTA Ligands. 1. Synthesis of Rigidified Ligands and Studies on the Effects of Alkyl Substitution on Acid−Base Properties and Conformational Mobility
    journal, December 2002

    • Ranganathan, Ramachandran S.; Pillai, Radhakrishna K.; Raju, Natarajan
    • Inorganic Chemistry, Vol. 41, Issue 25
    • DOI: 10.1021/ic025657v

    Polymethylated DOTA Ligands. 2. Synthesis of Rigidified Lanthanide Chelates and Studies on the Effect of Alkyl Substitution on Conformational Mobility and Relaxivity
    journal, December 2002

    • Ranganathan, Ramachandran S.; Raju, Natarajan; Fan, Helen
    • Inorganic Chemistry, Vol. 41, Issue 25
    • DOI: 10.1021/ic025695e

    Solution Dynamics and Stability of Lanthanide(III) ( S ) - 2-( p -Nitrobenzyl)DOTA Complexes
    journal, May 2004

    • Woods, Mark; Kovacs, Zoltan; Kiraly, Robert
    • Inorganic Chemistry, Vol. 43, Issue 9
    • DOI: 10.1021/ic0353007

    Chiral Recognition of α-Amino Acids by an Optically Active (2 S ,5 S ,8 S ,11 S )-2,5,8,11-Tetraethyl Cyclen Cobalt(III) Complex
    journal, January 2011

    • Tashiro, Shohei; Ogura, Yasuyo; Tsuboyama, Sei
    • Inorganic Chemistry, Vol. 50, Issue 1
    • DOI: 10.1021/ic101760k

    Properties, Solution State Behavior, and Crystal Structures of Chelates of DOTMA
    journal, September 2011

    • Aime, Silvio; Botta, Mauro; Garda, Zoltán
    • Inorganic Chemistry, Vol. 50, Issue 17
    • DOI: 10.1021/ic2012827

    Analysis of the Conformational Behavior and Stability of the SAP and TSAP Isomers of Lanthanide(III) NB-DOTA-Type Chelates
    journal, September 2011

    • Tircso, Gyula; Webber, Benjamin C.; Kucera, Benjamin E.
    • Inorganic Chemistry, Vol. 50, Issue 17
    • DOI: 10.1021/ic2012843

    Coupling Fast Water Exchange to Slow Molecular Tumbling in Gd 3+ Chelates: Why Faster Is Not Always Better
    journal, July 2013

    • Avedano, Stefano; Botta, Mauro; Haigh, Julian S.
    • Inorganic Chemistry, Vol. 52, Issue 15
    • DOI: 10.1021/ic400308a

    Gd(DOTAlaP): Exploring the Boundaries of Fast Water Exchange in Gadolinium-Based Magnetic Resonance Imaging Contrast Agents
    journal, June 2014

    • Boros, Eszter; Karimi, Shima; Kenton, Nathaniel
    • Inorganic Chemistry, Vol. 53, Issue 13
    • DOI: 10.1021/ic5008928

    Aggregation in Amphiphilic Macrocycle-Substituted Gd 3+ DOTA-Type Chelates Is Affected by the Regiochemistry of Substitution
    journal, February 2015

    • Webber, Benjamin C.; Cassino, Claudio; Botta, Mauro
    • Inorganic Chemistry, Vol. 54, Issue 5
    • DOI: 10.1021/ic5028724

    Albumin Binding, Relaxivity, and Water Exchange Kinetics of the Diastereoisomers of MS-325, a Gadolinium(III)-Based Magnetic Resonance Angiography Contrast Agent
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