Prof. Jens Hasserodt and his colleagues from Lyon, France discuss with us their discovery of a molecular system based on a pair of two structurally similar molecular iron(II) complexes that show different magnetic states (one diamagnetic, the other paramagnetic), which may be exploited for the development of more reliable and adaptable molecular probes for magnetic resonance imaging.

How did you get interested in this research project?

The interest came during discussions with colleagues from biology and medicine at the imaging centre ANIMAGE, and in particular with my collaborator Prof. Dr. Jacques Samarut, who pointed out to me the keen interest to be able to exploit magnetic resonance imaging (MRI) for its limitless penetration into the living body while offering very satisfactory and ever-increasing resolution. These colleagues are particularly interested in "functional imaging", i.e., the adaptation of a purely anatomical imaging method to the detection of specific biochemical activities with spatial and temporal resolution, in order to pursue research into the whole-body in vivo assessment of gene expression, and thus the phenotype in life and disease. 

It is important to mention at this point that a method called fMRI (functional MRI) exists already for a number of years and exploits a naturally-occurring contrast agent system that may exist in an "off" or "on" state according to its oxygenation state: heme in red blood cells. fMRI benefits from the high concentration of this "natural contrast agent" and is applied almost exclusively to the study of brain activity. But fMRI is not adaptable to biochemical phenomena other than blood oxygenation levels; it thus has a very narrow scope.

What is the most important result in the paper?

The discovery of a molecular system [based coincidentally on iron(II), as in heme] comprised of two structurally similar molecules that happen to exist in two different magnetic states, one diamagnetic, and thus mute in MRI, the other paramagnetic and hence a true MRI contrast agent (Figure 1). While this particular system may or may not result eventually in the design of a working probe, this discovery opens the doors to the development of molecular probes for MRI that will work in a wider range of applications.

In stark contrast to the narrow scope of fMRI, biologists need a generally applicable probe system that may be adapted to numerous enzyme activities while furnishing clear results. The here-presented system is a promising starting point for the design of a molecular probe for MRI that is invisible in MRI except when it encounters the enzymatic activity to which it is sensitive. Gadolinium-based approaches, as have been proposed by others, have the fundamental disadvantage that they cannot be totally muted in MRI. Thus, even if a working probe is one day presented to the scientific community, its application in the imaging of a living organism will always risk delivering ambiguous results. Often, established colleagues in the field point out in meetings that gadolinium-based probes give detection results that are dependent not only on the concentration and level of the target activity but also on the mere concentration of the (untouched) probe itself. By contrast, the here-presented iron(II)-based system, if developed into a working probe, can be present in high concentration in a particular tissue without modifying its contrast. The biologist or radiologist will not be misled.

Figure 1.While very similar in structure, iron complexes 1 and 2 differ by their low spin and high spin nature.   

Are there any particular challenges facing future research in this area? 

A major challenge is turning this system (or many possible alternative systems yet to be discovered) into a working probe that displays just the right stability to survive the harsh in vivo conditions (before being evacuated by the body by regular metabolic pathways), but also just the right lability in order to suffer fragmentation into the MRI-active form under the influence of the target (enzyme) activity. Also, the active form should have limited redox activity in order to minimise ROS (reactive oxygen species) generation and thus toxicity. Auto-immolable concepts for organic prodrug development are numerous and well-established while their development can be considered in its infancy with regard to metal coordination chemistry.