Responsive Agents

The MRI responsive agents are substances whose relaxivity depends on a particular physiological parameter of the microenvironment in which they are distributed (pH, temperature, enzymatic activity, ... ). Their application could give rise to the formation of images whose contrast depends on the particular value of the physiological parameter. The crucial problem to be solved is to be sure that the differences in the relaxation are due to changes of the relaxivity instead of the concentration of the agent.
Two main approaches are followed:

  • pH responsive agents

    They are agents based on DOTA-type Gd complexes in which the fourth arm is presenting a sulphonamidic function. The pK aof the N-H bond in such groups can be modified around the physiological values via suitable substitutions. The deprotonation of the N-H permits the entrance of the nitrogen atom into the coordination sphere of the complex, eventually changing its relaxivity. By comparing the T1 values obtained using two complexes that differ only in the pK ais possible to obtain a pH map. The assumption is that the two complexes show the same biodistribution.

  • Dual agents MRI/PET or SPECT

    The concentration of the agent is obtained via PET or SPECT. Two routes are explored:

    • The MRI complex has the same biodistribution of the PET/SPECT agent. Such approach is exploited on DOTA-type complexes by changing the metal for each different technique: for MRI the metal is Gd, in PET experiments the β-emitting 68Ga is used while 166Ho is the metal for SPECT. While Gd and Ho complexes probably share the same biodistribution, the same could not be said for the Ga complex (same charge of the ion, but different coordination capability).
    • The PET/SPECT reporter is covalently linked to the Gd complex. In this situation the dual agent contains both the MRI and PET/SPECT probes. The latter is mainly in his 'cold' form, the relative quantity of the 'hot' one depends both on the modality used and the characteristics of the isotope itself. Knowing the stoichiometric ratio between the radioactive isotope and the Gd is possible to extract the concentration of the agent, and transform the observed relaxation rates into pH maps.

Group Leaders:

Dario Longo Daniela Delli Castelli Giuseppe Digilio Eliana Gianolio Giuseppe Ferrauto