Enzyme responsive agents

One possible route to design enzyme-responsive agents is to synthesize paramagnetic inhibitors, whose binding to the active site of the protein can be signalled by the consequent relaxivity enhancement. An example of this approach has been provided by Anelli etal. who synthesized a linear Gd(III) complex bearing an arylsulfonamide moiety (Figure 28.9), which is a well-known inhibitor of carbonic anhydrase.32

In vitro experiments demonstrated that this complex binds quite strongly (KA of about 1.5 x 104) to the enzyme and its relaxivity in the bound form is about 5-fold higher than the free complex (27s_1mM_1 vs 5s~1mM~1 at 20 MHz). Unfortunately, an attempt to test the validity of this 'in vivo' approach failed, possibly owing to the small amount of enzyme circulating in the blood.

An alternative approach is to design Gd(III) complexes acting as substrate for a specific enzyme. Along this direction, an example has been provided by Lauffer etal., who prepared a Gd(III) chelate containing a phosphoric ester sensitive to the attack of the serum alkaline phosphatase (Figure 28.10).33 The hydrolysis yields the exposure of a hydrophobic moiety well suited to bind to HSA. Upon binding, there is an increase of the relaxivity as a consequence of the lengthening of the molecular reorientational time. This approach was used by the same research group for designing Gd(III) complexes sensitive to TAFI

Figure 28.9 Schematic representation of a ligand bearing an arylsulfonamide moiety whose Gd(III) complex acts as an inhibitor of carbonic anhydrase

Figure 28.9 Schematic representation of a ligand bearing an arylsulfonamide moiety whose Gd(III) complex acts as an inhibitor of carbonic anhydrase

Figure 28.10 The Gd(III) complex of this ligand has been proposed as an agent responsive to serum alkaline phosphatase

(thrombin-activatable fibrinolysis inhibitor), a carboxypeptidase B involved in the clot degradation.34

Also particles have been considered as enzymatic responsive agents. To this purpose, insoluble Gd(III) chelates have been synthesized by introducing, on the ligand surface, long aliphatic chains via an ester or a peptidic bond. The particles can be internalized into cells having a phagocytic activity and then degraded by the action of the proper enzyme which cleaves the bond between the Gd(III) chelate and the insolubilizing moiety. Thus, the increase of intra-cellular relaxivity becomes a function of the activity of the enzyme of choice. In principle, such an approach provides a representative example of 'responsive particles'. Immediately after the internalization, the particles act as negative T2 agents because they affect the bulk magnetic susceptibility. Then, their dissolution yields soluble Gd(III) chelates which act as positive T1 agents.35

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