Chimeric mouse model for MRI contrast agent evaluation

Abstract

Purpose: While rodents are the primary animal models for contrast agent evaluation, rodents can potentially misrepresent human organ clearance of newly developed contrast agents. For example, gadolinium (Gd)-BOPTA has ~50% hepatic clearance in rodents, but ~5% in humans. This study demonstrates the benefit of chimeric mice expressing human hepatic OATPs (organic anion-transporting polypeptides) to improve evaluation of novel contrast agents for clinical use. Methods: FVB (wild-type) and OATP1B1/1B3 knock-in mice were injected with hepatospecific MRI contrast agents (Gd-EOB-DTPA, Gd-BOPTA) and nonspecific Gd-DTPA. T 1 -weighted dynamic contrast-enhanced MRI was performed on mice injected intravenously. Hepatic MRI signal enhancement was calculated per time point. Mass of gadolinium cleared per time point and percentage elimination by means of feces and urine were also measured. Results: Following intravenous injection of Gd-BOPTA in chimeric OATP1B1/1B3knock-in mice, hepatic MRI signal enhancement and elimination by liver was more reflective of human hepatic clearance than that measured in wild-type mice.Gd-BOPTA hepatic MRI signal enhancement was reduced to 22% relative to wildtype mice. Gd-BOPTA elimination in wild-type mice was 83% fecal compared with 32% fecal in chimeric mice. Hepatic MRI signal enhancement and elimination for Gd-EOB-DTPA and Gd-DTPA were similar between wild-type and chimeric cohorts. Conclusion: Hepatic MRI signal enhancement and elimination of Gd-EOB-DTPA, Gd-BOPTA, and Gd-DTPA in chimeric OATP1B1/1B3 knock-in mice closely mimics that seen in humans. This study provides evidence that the chimeric knock-in mouse is a more useful screening tool for novel MRI contrast agents destined for clinical use as compared to the traditionally used wild-type models. K E Y W O R D S chimera, gadolinium, humanized model, MRI, OATP, preclinical 388 | MIR et al.

Divalent Manganese Complexes as Potential Replacements for Gadolinium-Based Contrast Agents

“…Amphiphilic anionic complexes such as Gd-EOB-DTPA (gadoxetic acid) are taken up by hepatocytes via organic anion transporter peptides to varying degrees. 52 Mn 2+ chelates based on EDTA, PyC3A, and CDTA-monoamide have been shown to undergo different degrees of 52 Mn-labeled Mn-PyC3A (top panels) or Mn-DPDP (bottom panels). Mass dose was 0.2 mmol/kg for [ 52 Mn]Mn-PyC3A and 0.01 mmol/kg for [ 52 Mn]Mn-DPDP.…”

“…52 Mn 2+ chelates based on EDTA, PyC3A, and CDTA-monoamide have been shown to undergo different degrees of 52 Mn-labeled Mn-PyC3A (top panels) or Mn-DPDP (bottom panels). Mass dose was 0.2 mmol/kg for [ 52 Mn]Mn-PyC3A and 0.01 mmol/kg for [ 52 Mn]Mn-DPDP. Panel A shows dynamic images from 1 to 60 minutes postinjection, whereas panel B (different scale) shows images from 4 hours to 7 days postinjection.…”

“…Four thorough analyses were performed in rats that demonstrated that Mn from Mn-PyC3A was more completely eliminated than the most stable macrocyclic GBCA, Gd-DOTA. 64,66 Mn-PyC3A was radiolabeled with 52 Mn, a positron-emitting isotope with a 5.6-day half-life. Quantitative whole-body Mn biodistribution analysis was performed by measuring 52 Mn activity in 40 different tissues 1 day (n = 10) and 7 days (n = 14) after injection of 2.0 mmol/kg [ 52 Mn]Mn-PyC3A.…”

“…64,66 Mn-PyC3A was radiolabeled with 52 Mn, a positron-emitting isotope with a 5.6-day half-life. Quantitative whole-body Mn biodistribution analysis was performed by measuring 52 Mn activity in 40 different tissues 1 day (n = 10) and 7 days (n = 14) after injection of 2.0 mmol/kg [ 52 Mn]Mn-PyC3A. For comparison, the 1-day and 7-day biodistributions of Gd-DOTA were performed in another set of rats (n = 6 per time point) that received an equal dose and were housed under identical conditions.…”

Organic Anion Transporting Polypeptide 1B1 Is a Potential Reporter for Dual MR and Optical Imaging

“…Estradiol-17β-glucuronide and estrone-3-sulfate are two substrates that are transported preferentially by OATP1B1, whereas cholecystokinin octa-peptide (CCK-8) is a substrate whose transport is specific to OATP1B3 [11][12][13][14]. Previous inhibition studies and activity modification via the protein kinase C pathway showed that Gd-BOPTA is transported through OATPs and that its efflux from hepatocytes is via multiple resistanceassociated protein 3 [15,16]. However, other results identified human OATP1B1 and OATP1B3 expression in Slco1a/1b knockout mice and that OATP1B1/1B3 could not fully rescue the transportation of Gd-BOPTA in knockout mice [17].…”