Gadolinium-free Magnetic Resonance Imaging of the Liver via an Oatp1-Targeted Manganese(III) Porphyrin

Nivin N Nyström; Hanlin Liu; Francisco M Martinez; Xiao-An Zhang; Timothy J Scholl; John A Ronald

doi:10.1021/acs.jmedchem.2c00500

Gadolinium-free Magnetic Resonance Imaging of the Liver via an Oatp1-Targeted Manganese(III) Porphyrin

J Med Chem. 2022 Jul 19. doi: 10.1021/acs.jmedchem.2c00500. Online ahead of print.

Authors

Nivin N Nyström^{1

2}, Hanlin Liu^{3

4}, Francisco M Martinez², Xiao-An Zhang^{3

4}, Timothy J Scholl^{1

2

5}, John A Ronald^{1

2

6}

Affiliations

¹ Department of Medical Biophysics, University of Western Ontario, London N6A 3K7, Ontario, Canada.
² Imaging Research Laboratories, Robarts Research Institute, Western University, London N6A 3K7, Ontario, Canada.
³ Department of Chemistry, University of Toronto, Toronto M5S 1A4, Ontario, Canada.
⁴ Department of Physical and Environmental Sciences, University of Toronto, Toronto M5S 1A4, Ontario, Canada.
⁵ Ontario Institute for Cancer Research, Toronto M5G 0A3, Ontario, Canada.
⁶ Lawson Health Research Institute, London N6C 2R5, Ontario, Canada.

PMID: 35852350
DOI: 10.1021/acs.jmedchem.2c00500

Abstract

Controversy surrounding gadolinium-based contrast agents (GBCAs) has rendered their continued utility highly contentious, but the liver-specific GBCA Gd(III) ethoxybenzyl-diethylene triamine pentaacetic acid (Gd(III)-EOB-DTPA) remains in use because it provides unique diagnostic information that could not be obtained by any other means. To address the need for an alternate liver-specific MRI probe, we synthesized Mn(III) 20-(4-ethoxyphenyl) porphyrin-5,10,15-tricarboxylate (Mn(III)TriCP-PhOEt), which exhibited significantly higher r₁ relaxivity than Gd(III)-EOB-DTPA in vitro, while also targeting hepatocyte-specific organic anion-transporting polypeptide 1 (Oatp1) channels as a marker of viability. In mice, Mn(III)TriCP-PhOEt resulted in significant and specific increases in liver signal intensity on T₁-weighted images and significant decreases in liver T₁ time relative to pre-contrast measurements. Our findings suggest that Mn(III)TriCP-PhOEt operates as a specific and sensitive MR probe for Oatp1-targeted imaging in vivo.