BLANC - Blanc

Enzyme-Activated Contrast Agents for Magnetic Resonance Imaging – ENZYMRI

Submission summary

The evolution of Magnetic Resonance Imaging into one of the most prominent clinical diagnostic modalities has been largely assisted by the use of paramagnetic contrast agents. Nowadays, imaging of molecular events at the cellular level starts to become accessible. Molecular Imaging requires probes that are specific to a particular molecular event, which places chemistry into a vital position in the development of this revolutionary technology. Despite several attempts, the in vivo MRI detection of enzymes remains a challenge. This proposal offers a general approach to the rational conception of enzyme responsive MRI probes. We will synthesize GdIII complexes that change their proton relaxivity, thus MRI efficiency in the presence of an enzyme of choice. These agents are designed to function on the basis of the 'self-immolative' mechanism, a concept applied in 'Antibody Directed Enzyme Prodrug Therapy' or 'Gene Directed Enzyme Prodrug Therapy'. The contrast agent is activated or deactivated by attack of a specific enzyme which initiates a self-immolation process in a defined part of the molecule. This cascade reaction results in structural changes of the complex which in turn affects its relaxivity and result in an enzymatic MRI response. In order to target a large variety of enzyme activity, the probes have modulable structure consisting of three moieties: (i) the coordinating unit around the Gd, (ii) the chain that undergoes self-immolation on enzyme activation and (iii) the substrate for a specific enzyme which temporarily protects the self-immolative chain. For GdIII complexation, we will explore both macrocyclic (DOTA-type) and acyclic (DTPA-type) chelators, with amino glycine or an aminal for coupling to the self-immolative linker. The self-immolative mechanism is based on the intrinsic instability of benzyloxy carbamates possessing an electron donor substituent in ortho or para position. P-hydroxy mandelic acid derivatives will also be used as self-immolative linkers, with the advantage of easy coupling to macromolecules via the acid function. The substrate can be any moiety that transitionally reduces the electron donor capabilities of the substituent. This general approach allows to target a large variety of enzymes (esterase, lipase, glycosidase, …). Among the different parameters determining relaxivity of a GdIII complex, rotational dynamics and hydration number are the most accessible to modification in an enzymatically activated self-immolative process. One class of the GdIII complexes is designed to give a relaxivity response to enzymes which is related to a change in the size, hence in the rotational motion of the molecule. The size change is realized via enzymatique cleavage of the chelates from medium-sized or macromolecular (dendrimeric, protein bound, etc.) entities. Another approach is represented by compounds which undergo a hydration number change on enzyme activation. The new GdIII complexes will be characterized with regard to MRI contrast agent applications. Proton relaxivities will be measured as a function of the magnetic field. 17O NMR will be used to assess hydration number and water exchange. The project specifically aims at the understanding of the functioning of these potential enzymatic contrast agents at the molecular level. We will assess all parameters that play a role in the enzyme-promoted relaxivity change. We believe that this understanding will allow us to improve the systems on a rational basis. The most promising compounds will be tested in cell lines and small animal MRI studies. Lanthanide complexes other than GdIII (EuIII, DyIII, YbIII, TmIII) containing slow-exchanging amide protons have been widely investigated as PARACEST agents. By replacing the GdIII with one of these lanthanide ions in our enzyme-responsive systems, we might obtain potential, enzyme-responsive agents for PARACEST imaging. These aspects will be also addressed. In addition to an in vivo application, the proposed systems are prospective probes for High or Medium Throughput Screening of enzyme inhibitors by MRI. MRI represents a viable alternative to currently used high throughput screening modalities. The detection by MRI is much less prone to interferences as compared to spectrophotometric techniques, and is more convenient in terms of safety than radioactive probes. An important aspect of the project is to combine expertise from various fields, such as bioorganic chemistry and enzyme mechanisms, synthesis of prodrugs, physico-chemical characterization of MRI contrast agents and MRI technology. Through these interactions and in synergy with the industrial partner, we will develop novel, highly efficient imaging probes based on innovative coordination and bioconjugation chemistry. This project, submitted in 2006 for the first time in the programme 'ANR blanc', has been improved according to the remarks and suggestions of the referees.

Project coordination

Jean Claude BELOEIL (Organisme de recherche)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.


Help of the ANR 450,000 euros
Beginning and duration of the scientific project: - 36 Months

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