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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, 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. https://doi.org/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. https://doi.org/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 = {Tue Feb 27 00:00:00 EST 2018},
month = {Tue Feb 27 00:00:00 EST 2018}
}

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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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In-Cell Protein Structures from 2D NMR Experiments
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journal, February 2011

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  • Angewandte Chemie, Vol. 123, Issue 11
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Gadolinium—a specific trigger for the development of nephrogenic fibrosing dermopathy and nephrogenic systemic fibrosis?
journal, June 2006

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

  • Zhang, Zhaoda; Greenfield, Matthew T.; Spiller, Marga
  • Angewandte Chemie, Vol. 117, Issue 41
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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, Vol. 120, Issue 26
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Heteroditopic Binding of Magnetic Resonance Contrast Agents for Increased Relaxivity
journal, February 2011

  • Zhang, Zhaoda; Kolodziej, Andrew F.; Greenfield, Matthew T.
  • Angewandte Chemie, Vol. 123, Issue 11
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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
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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
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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


Brain gadolinium deposition, hyperintense MRI signals, and resonance contrast agents
journal, October 2018


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

Gadolinium(III) Chelates as MRI Contrast Agents:  Structure, Dynamics, and Applications
journal, September 1999

  • 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
journal, October 1994

  • Aime, Silvio; Batsanov, Andrei S.; Botta, Mauro
  • Inorganic Chemistry, Vol. 33, Issue 21
  • DOI: 10.1021/ic00099a020

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

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

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
journal, August 2007

  • Caravan, Peter; Parigi, Giacomo; Chasse, Jaclyn M.
  • Inorganic Chemistry, Vol. 46, Issue 16
  • DOI: 10.1021/ic700686k

Optimization of the Relaxivity of MRI Contrast Agents:  Effect of Poly(ethylene glycol) Chains on the Water-Exchange Rates of Gd III Complexes
journal, October 2001

  • Doble, Dan M. J.; Botta, Mauro; Wang, Jay
  • Journal of the American Chemical Society, Vol. 123, Issue 43
  • DOI: 10.1021/ja011085m

The Interaction of MS-325 with Human Serum Albumin and Its Effect on Proton Relaxation Rates
journal, March 2002

  • Caravan, Peter; Cloutier, Normand J.; Greenfield, Matthew T.
  • Journal of the American Chemical Society, Vol. 124, Issue 12
  • DOI: 10.1021/ja017168k

Circularly Polarized Luminescence of Curium: A New Characterization of the 5f Actinide Complexes
journal, September 2012

  • Law, Ga-Lai; Andolina, Christopher M.; Xu, Jide
  • Journal of the American Chemical Society, Vol. 134, Issue 37
  • DOI: 10.1021/ja306354n

Direct Measurement of the Mn(II) Hydration State in Metal Complexes and Metalloproteins through 17 O NMR Line Widths
journal, October 2013

  • Gale, Eric M.; Zhu, Jiang; Caravan, Peter
  • Journal of the American Chemical Society, Vol. 135, Issue 49
  • DOI: 10.1021/ja4094132

Lanthanide(III) Complexes with a Reinforced Cyclam Ligand Show Unprecedented Kinetic Inertness
journal, December 2014

  • Rodríguez-Rodríguez, Aurora; Esteban-Gómez, David; Tripier, Raphaël
  • Journal of the American Chemical Society, Vol. 136, Issue 52
  • DOI: 10.1021/ja511331n

Chiral Tetraazamacrocycles Having Four Pendant-Arms
journal, June 2009

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Works referencing / citing this record:

The Use of the Macrocyclic Chelator DOTA in Radiochemical Separations: The Use of the Macrocyclic Chelator DOTA in Radiochemical Separations
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A Bishydrated, Eight–Coordinate Gd(III) Complex with Very Fast Water Exchange: Synthesis, Characterization, and Phantom MR Imaging
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Ligand design strategies to increase stability of gadolinium-based magnetic resonance imaging contrast agents
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Synthesis of chiral nine and twelve-membered cyclic polyamines from natural building blocks
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The use of the macrocyclic chelator DOTA in radiochemical separations
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Synthesis of chiral nine and twelve-membered cyclic polyamines from natural building blocks
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