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. 2019 Dec 20:2019:8356931.
doi: 10.1155/2019/8356931. eCollection 2019.

Fe-HBED Analogs: A Promising Class of Iron-Chelate Contrast Agents for Magnetic Resonance Imaging

Brian C Bales  1 , Brian Grimmond  1 , Bruce F Johnson  1 , M Todd Luttrell  1 , Dan E Meyer  1 , Tatyana Polyanskaya  1 , Michael J Rishel  1 , Jeannette Roberts  1
Affiliations

Fe-HBED Analogs: A Promising Class of Iron-Chelate Contrast Agents for Magnetic Resonance Imaging

Brian C Bales et al. Contrast Media Mol Imaging. .

Abstract

Contrast-enhanced magnetic resonance imaging is an essential tool for disease diagnosis and management; all marketed clinical magnetic resonance imaging (MRI) contrast agents (CAs) are gadolinium (Gd) chelates and most are extracellular fluid (ECF) agents. After intravenous injection, these agents rapidly distribute to the extracellular space and are also characterized by low serum protein binding and predominant renal clearance. Gd is an abiotic element with no biological recycling processes; low levels of Gd have been detected in the central nervous system and bone long after administration. These observations have prompted interest in the development of new MRI contrast agents based on biotic elements such as iron (Fe); Fe-HBED (HBED = N,N'-bis(2-hydroxyphenyl)ethylenediamine-N,N'-diacetic acid), a coordinatively saturated iron chelate, is an attractive MRI CA platform suitable for modification to adjust relaxivity and biodistribution. Compared to the parent Fe-HBED, the Fe-HBED analogs reported here have lower serum protein binding and higher relaxivity as well as lower relative liver enhancement in mice, comparable to that of a representative gadolinium-based contrast agent (GBCA). Fe-HBED analogs are therefore a promising class of non-Gd ECF MRI CA.

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Conflict of interest statement

The authors declare that they have no conflicts of interest.

Figures

Figure 1
Figure 1
Fe chelates evaluated as ECF MR CA: (a) Fe-HBED (Fe-1); (b) Fe-HBEDP (Fe-3); (c) Fe-SHBED (Fe-2); (d) Fe-HBEDP-(CH2OH)2 (Fe-4); (e) Fe-HBEDP-(CH2OH)3 (Fe-5).
Figure 2
Figure 2
General synthetic scheme for HBEDP analogs 3, 4, and 5.
Figure 3
Figure 3
Air oxidation of ascorbic acid catalyzed by Fe-3 and Fe-5 and positive control Fe-EDTA.
Figure 4
Figure 4
Tissue signal enhancement of contrast agents in the kidney cortex and liver in naïve mice. Quantified SE is given for Fe-1, Fe-2, and Gd-1 in the kidney cortex (a) and in the liver (c). formula image Mean with value; formula image individual data points. Data labels are the mean. Corresponding images of preinjection (left) and 5 minutes postinjection (right) for the mouse representing median enhancement for each agent group for the kidney (b) and liver (d). The window and level of the images are scaled for uniformity. Arrows denote the left kidney cortex (b) and liver (d).
Figure 5
Figure 5
Signal enhancement in the kidney cortex evaluated in the tumor mouse model. (a) SE (5 min/pre) of Fe-2 to Fe-5 and Gd-1 in the left kidney cortex. formula image Mean; formula image individual data points. Data labels are the mean. The SE afforded by Gd-1 is greater than Fe-2 and Fe-5 (p ≤ 0.05). Fe-3 SE is greater than Fe-2 SE (p=0.007). (b) Preinjection (left) and 5 minutes postinjection (right) images for the mouse representing median enhancement for each agent group. The window and level of the images are scaled for uniformity. Arrows denote the left kidney cortex.
Figure 6
Figure 6
Performance of the iron agents in imaging of the mouse liver. (a) Enhancement ratios (post/pre) of the 4 agents in the liver. Fe-3 is significantly different than Fe-2 (p=0.006), and other differences are not significant (p > 0.1). formula image Mean ± 95% confidence interval; formula image individual data points. (b) Preinjection (left) and 5 minutes postinjection (right) images for the mouse representing median enhancement for each agent group. The window and level of the images are scaled for uniformity. Arrows denote the liver regions used for analysis.
Figure 7
Figure 7
Performance of the iron agents in imaging of the C6 glioma tumor model. (a) Enhancement ratios (post/pre) of 4 iron chelate agents. There is no significant difference in the means of tumor enhancement for the iron chelates (p > 0.06), though Fe-3 trended higher, as was also the case for the kidney cortex. The differences between Gd-1 and all the iron chelates were significant (p < 0.001). formula image mean ± 95% confidence interval; formula image individual data points. (b) Preinjection (left) and 5 minutes postinjection (right) images for the tumor-bearing mouse representing median enhancement for each agent group. The window and level of the images are scaled for uniformity. Arrows indicate the position of the subcutaneous tumor.
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