Molecular Imaging

Do you want to know about advance imaging techniques? You are on the right page. In this article, you will learn about molecular biology, which is related to the molecular basis of any biological activity between the human cells. For instance, it can be interactions, molecular synthesis, mechanism, and much more.

The principle

A current possibility of research and development is the application of magnetic resonance imaging at the cellular or subcellular scale as a variant of what is called molecular imaging, which makes it possible to visualize in a non-invasive manner. Many processes are taking place on this scale, such as the expression of a gene, a receptor, the functioning of an enzyme system, etc. It is functional imagery which allows, due to a "tracer," to study the functioning of the organs. It is called molecular or metabolic imaging because we can imagine the fate of a molecule in the body.

Molecular imaging is already used in nuclear medicine (by the use of radioactive isotopes). It is a very sensitive technique, but irradiating and not very resolving. In particular, it uses an effective tracer, available today on the market (18FDG), which makes it possible to trace the consumption of glucose in cancer cells. It is used in clinical routine; this molecular imaging tracer represents a considerable contribution in medical diagnosis, in particular in oncological applications.

We now wish to use tracers as contrast agents, but for molecular imaging by magnetic resonance, a non-irradiating technique and allowing access to high spatial resolutions. Currently, there are already tracers of macrophage activity, which allow, for example, detect inflammatory lesions associated with multiple sclerosis. These tracers have already been evaluated in phase II clinical trials. MRI contrast agents for molecular imaging have also been developed to monitor angiogenic processes (appearance of new vessels associated with malignant tumors and their metastases).

Designing an MRI tracer for molecular imaging: a chemist's challenge

The design of MRI tracers for molecular imaging requires linking a molecular structure called pharmacophore to a contrastophore, via a "spacer."

We will vary the pharmacophore to optimize its affinity and selectivity for a specific target. By also varying the contrastophore, we always seek to optimize the relaxivity, which is to say the efficiency of the tracer on the MRI signal. Indeed, for existing contrast media, it is necessary to accumulate the tracer locally at concentrations of 10 to 100 μM to obtain a signal detectable by MRI. However, the concentration of cellular receptors involved in pathological processes is of the order of 1 µM to 1 nM. To generate a specific contrast, it is necessary to obtain local concentrations of contrast agent comparable to that of the biological target studied.

Consequently, the sensitivity of the contrast agents should be increased by several orders of magnitude in order to be able to visualize what is happening on the scale of molecular imaging. The spacer is also interesting because it can make it possible to modify the physicochemical properties of the product, such as solubility or viscosity, but also to improve accessibility to a well-defined area, for example, the passage of the blood-brain barrier. 

Molecular MRI: Towards the early diagnosis of Alzheimer's disease

Research has led to the finding of an effective first tracer, consisting of a gadolinium complex (contrastophore) to which a peptide (pharmacophore) has been attached. They are capable of recognizing beta-amyloid plaques these plaques that accumulate abnormally in the Alzheimer's disease. A putrescine structure is grafted onto the spacer that binds them together, an amino structure that will promote the passage of the blood-brain barrier. This tracer was tested on transgenic mice models of Alzheimer's disease, whose brain was analyzed by MRI; MRI images have clearly shown the presence of beta-amyloid plaques characteristic of the disease.

Molecular MRI: Towards the early diagnosis of ovarian cancer

Other research has focused on the detection of cancer cells in certain cancers, including ovarian cancer. This "silent and killer" cancer is generally only detected at late stages. Today, it represents a notable challenge in diagnostics. These cells are distinguished from healthy cells by the overexpression of folic acid receptors on their membranes. These receptors are also interesting targets for carrying anticancer drugs.

The goal is to detect them by MRI using a tracer, in the hope of early diagnosis. For this, the strategy envisaged is to graft folic acid onto a contrast agent derived from the P730Gd platform, hoping to use the natural mechanism of endocytosis, by which the cancer cell will be able to internalize the tracer.

For verification, comparative tests were carried out: two contrast agents, P866 and P999, were synthesized from the P730 platform seen previously. Their structures are identical, with the difference that on one of them, P866, a "folate residue" was grafted (by reaction with folic acid), while the other product, P999, does not contain this residue and therefore constitutes a control molecule.

A first in vitro experiment was carried out on human tumor cells. It demonstrated a particular affinity of the tracer comprising folate with respect to these cells. 

To now verify the effectiveness of the method for MRI medical imaging, in vivo tests have been carried out in mice having KB tumors overexpressing the folic acid receptor, to which this new P866 tracer has been injected. The concentration of gadolinium in the tumor tissues was measured four hours after the injection, and it is found that this tracer specifically accumulates in the organs, unlike the control tracer P999. However, this selectivity is only obtained with injected doses of less than 10 μmol of gadolinium ions per kilogram. Beyond (30 µmol per kilogram), there is no longer any selectivity 

And unfortunately, if you stay below this dose, the MRI signal is not intense enough. 

The loss of information at 30 µmol per kilogram can be explained. The excess of tracer injected drowns in a background noise the specific signal coming from tracer molecules that are well linked to the tumor receptors. This is a problem of sensitivity of the measurement probes, which still needs to be improved. 

Molecular MRI to visualize the processes in cells, therefore, remains a challenge. Researchers still have several cards to play, notably with the use of image processing software; or the development of more efficient contrastophores, in particular, nanoparticulate structures based on "superparamagnetic" iron oxides.

Author: Vicki Lezama