CM-101: Type I Collagen–targeted MR Imaging Probe for Detection of Liver Fibrosis

Abstract

Purpose To evaluate the biodistribution, metabolism, and pharmacokinetics of a new type I collagen-targeted magnetic resonance (MR) probe, CM-101, and to assess its ability to help quantify liver fibrosis in animal models. Materials and Methods Biodistribution, pharmacokinetics, and stability of CM-101 in rats were measured with mass spectrometry. Bile duct-ligated (BDL) and sham-treated rats were imaged 19 days after the procedure by using a 1.5-T clinical MR imaging unit. Mice were treated with carbon tetrachloride (CCl) or with vehicle two times a week for 10 weeks and were imaged with a 7.0-T preclinical MR imaging unit at baseline and 1 week after the last CCl treatment. Animals were imaged before and after injection of 10 µmol/kg CM-101. Change in contrast-to-noise ratio (ΔCNR) between liver and muscle tissue after CM-101 injection was used to quantify liver fibrosis. Liver tissue was analyzed for Sirius Red staining and hydroxyproline content. The institutional subcommittee for research animal care approved all in vivo procedures. Results CM-101 demonstrated rapid blood clearance (half-life = 6.8 minutes ± 2.4) and predominately renal elimination in rats. Biodistribution showed low tissue gadolinium levels at 24 hours (<3.9% injected dose [ID]/g ± 0.6) and 10-fold lower levels at 14 days (<0.33% ID/g ± 12) after CM-101 injection with negligible accumulation in bone (0.07% ID/g ± 0.02 and 0.010% ID/g ± 0.004 at 1 and 14 days, respectively). ΔCNR was significantly (P < .001) higher in BDL rats (13.6 ± 3.2) than in sham-treated rats (5.7 ± 4.2) and in the CCl-treated mice (18.3 ± 6.5) compared with baseline values (5.2 ± 1.0). Conclusion CM-101 demonstrated fast blood clearance and whole-body elimination, negligible accumulation of gadolinium in bone or tissue, and robust detection of fibrosis in rat BDL and mouse CCl models of liver fibrosis. RSNA, 2017 Online supplemental material is available for this article.

Extracellular matrix alterations in low‐grade lung adenocarcinoma compared with normal lung tissue by imaging mass spectrometry

“…In conclusion, ECM IMS, including the associated in‐solution workflows, is an important advance towards understanding low‐grade adenocarcinoma represented in clinically preserved FFPE specimens. Noninvasive imaging probes have been developed that target collagen 1 or contrast against collagen type I . We suggest that the molecular data produced by ECM IMS are useful in pinpointing specific peptide components of collagen altered by emergent adenocarcinoma.…”

“…New tools for noninvasive imaging of ECM in fibrotic processes have recently been developed, yet there is still a gap in defining disease‐specific ECM deposition for molecular targeting. ECM proteins are challenging for mass spectrometry (MS) analyses due to lower basic amino acid content and extensive post translational modifications that include cross‐linking.…”

Molecular imaging of fibrosis: recent advances and future directions

“…To enable clinical translation of this technology, an improved probe, CM-101, was developed (44). CM-101 uses the more stable macrocyclic gadolinium chelate, Gd-DOTA, and has improved pharmacokinetic properties compared with EP-3533, with decreased blood half-life, and less probe retention in the liver, bone, and kidneys.…”

Molecularly Targeted MR Imaging Agent in Liver Fibrosis: High Sensitivity and Low Gadolinium Mean High Translational Potential

“…In this issue of Radiology, Farrar et al (9) have improved on their firstgeneration agent, EP-3533, by synthesizing the same collagen-targeting peptide but now attaching it to a more All results were corroborated by concurrent ex vivo immunostaining for the presence of collagen and fibrosis. Molecular MR imaging is an inherently daunting task.…”

“…Structural MR imaging relies on the detection of water protons, which are at a concentration of 110 molar. To detect limited molecular species (in micromolar concentrations), the low sensitivity of targeted MR imaging contrast agents, particularly gadolinium-based agents, can be overcome through the addition of multiple gadolinium species, as done by Farrar et al (9), with appropriate pharmacokinetic tuning to enable suitable contrast. Another approach is through chemical exchange saturation transfer imaging, where no dose-or a homeopathic dose-of contrast material is administered (10).…”