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

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

doi:10.1155/2019/8356931

Brian C Bales, Michael J Rishel + Show 6 more

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https://doi.org/10.1155/2019/8356931

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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.

Highlights

Contrast-enhanced magnetic resonance imaging is an “essential tool for disease diagnosis and management” [1]
Marketed clinical magnetic resonance contrast agents are Gd chelates. It has recently been observed in humans and preclinical models that low levels of Gd can be detected in tissue, in the central nervous system following administration of multiple doses of gadoliniumbased contrast agents (GBCA) [2,3,4]
T1-weighted image contrast from magnetic resonance imaging (MRI) CA depends on the ability of the CA to shorten the longitudinal relaxation time of protons on nearby water molecules; this capability is typically reported as r1 relaxivity and given in units of mM− 1·s− 1. e measured relaxivity represents contributions from 3 different types of water protons, as shown in the following equation [20, 33, 34]: r1 rI1S + rS1S + rO1 S, (1)

Summary

Introduction

Contrast-enhanced magnetic resonance imaging is an “essential tool for disease diagnosis and management” [1]. Marketed clinical magnetic resonance contrast agents are Gd chelates It has recently been observed in humans and preclinical models that low levels of Gd can be detected in tissue, in the central nervous system following administration of multiple doses of gadoliniumbased contrast agents (GBCA) [2,3,4]. Intravenous administration of the chelate iron gluconate (125 mg or 250 mg Fe) is a welltolerated intervention for anemia [14, 15] In this chelate, Fe is weakly held by gluconate, consistent with the intention to deliver iron in a usable form to relieve anemia; this reduces concerns associated with any escape of low levels of free Fe from a rapidly excreted iron-based contrast agent (IBCA) in which the Fe is tightly chelated

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