Development of a Suite of Gadolinium-Free OATP1-Targeted Paramagnetic Probes for Liver MRI
Sean W. McRae, Michael D. Cleary, Daniel DeRoche, Francisco M. Martínez, Ying Xia, Peter Caravan, Eric M. Gale, John A. Ronald, Timothy J. Scholl
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 T 1 -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 T 1 -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.