Development of a Suite of Gadolinium-Free OATP1-Targeted Paramagnetic Probes for Liver MRI

J Med Chem. 2023 May 25;66(10):6567-6576. doi: 10.1021/acs.jmedchem.2c01561. Epub 2023 May 9.

Abstract

Five amphiphilic, anionic Mn(II) complexes were synthesized as contrast agents targeted to organic anion transporting polypeptide transporters (OATP) for liver magnetic resonance imaging (MRI). The Mn(II) complexes are synthesized in three steps, each from the commercially available trans-1,2-diaminocyclohexane-N,N,N',N'-tetraacetic acid (CDTA) chelator, with T1-relaxivity of complexes ranging between 2.3 and 3.0 mM-1 s-1 in phosphate buffered saline at an applied field strength of 3.0 T. Pharmacokinetics were assessed in female BALB/c mice by acquiring T1-weighted images dynamically for 70 min after agent administration and determining contrast enhancement and washout in various organs. Uptake of Mn(II) complexes in human OATPs was investigated through in vitro assays using MDA-MB-231 cells engineered to express either OATP1B1 or OATP1B3 isoforms. Our study introduces a new class of Mn-based OATP-targeted contrast that can be broadly tuned via simple synthetic protocols.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Female
  • Humans
  • Liver* / diagnostic imaging
  • Liver-Specific Organic Anion Transporter 1
  • Magnetic Resonance Imaging / methods
  • Membrane Transport Proteins
  • Mice
  • Organic Anion Transporters*
  • Organic Anion Transporters, Sodium-Independent
  • Solute Carrier Organic Anion Transporter Family Member 1B3

Substances

  • Liver-Specific Organic Anion Transporter 1
  • Solute Carrier Organic Anion Transporter Family Member 1B3
  • Organic Anion Transporters
  • Membrane Transport Proteins
  • Organic Anion Transporters, Sodium-Independent