Manganese complexes for multimodal PET/MRI imaging: progress of METRICS project

Hybrid Imaging is the new important step-forward that is becoming established, aimed at improving the diagnostic procedures by nuclear imaging through the “fusion” between two of the imaging modalities already available nowadays, such as Positron Emission Tomography (PET) and Magnetic Resonance Imaging (MRI). This new approach is based upon the intrinsic difference (i.e. information content from both procedures) relied on the different physical process exploited, in order to achieve a collection of both diagnostic information obtained, thus generating images which are fundamentally different in nature. While MRI allows for obtaining the morphological information of organ tissues based upon the relaxation properties of the hydrogen atoms therein, PET is, instead, a molecular imaging modality based on the use of radiolabeled compounds, able to interact with cellular processes thus obtaining functional information at the molecular level. Therefore, by combining images (i.e. information) having such a diverse diagnostic content, a deeper understanding of the clinical picture could be obtained. However, it should be noted that, to date, does exists an inescapable diagnostic mismatch between PET and MRI, due to the diversity between the chemical composition of both probes used, i.e. the paramagnetic contrast and radioactive agents, respectively. That results in a hard-to-achieve molecular “fusion” between the information got from both nuclear and magnetic resonance signals. The key approach would clearly be to find out a compound having paramagnetic properties and the corresponding radioactive agent based upon the same molecular probe. Therefore having both the same chemical composition and molecular structure, thus interacting with the same molecular target. According to the approach here outlined, this result corresponds to the endeavor of getting a fundamental step- forward in the process of achieving a “true” molecular matching between MRI and PET chemical probes used, that might enhance the power of the combined diagnostic modalities. The ongoing research program METRICS (acronym for Multimodal pET/mRI imaging with Cyclotron-produced 51/52Mn iSotopes), funded by the INFN fifth National Scientific Committee (CSN5), was born with the aim to produce cyclotron-based Mn-51 and Mn-52 radionuclides and also to develop an experimental strategy to attain a genuine molecular fusion between PET and MRI. Since the transition element manganese owns stable paramagnetic isotopes, as well as a couple of positron-emitting radioisotopes, it turns out that it constitutes an ideal candidate for pursuing the scope of the METRICS project. We must consider that manganese, in its free (i.e. ion) form, is neurotoxic (LD% = 0,22 mmol/kg for rat). It is therefore important to find stable Mn-complexes that preserve the paramagnetic character while preventing the premature release of the metal ions in the body. For this purpose, the reactivity of the Mn2 + ion towards various classes of ligands has been investigated. Mn(II) complexes were prepared and characterized looking for the most robust ligand arrangement, capable of stabilizing the Mn2+ ion in a biological environment. Moreover, to get an isolation of the derivatives that could be able to mimic the behavior of perfusion imaging agents widely employed in nuclear scintigraphy