Self-Assembling Peptide-Based High-Relaxivity Targeted MRI Contrast Agents.

Concentration-dependent increases in relaxivity (r1) were found to be induced by self-assembly when Fmoc is adjacent to tryptophan in peptide-based MRI contrast agents featuring Gd-DOTA. A series of di- and tri-peptides were synthesized to test the effect of ionic strength, N-terminal substituent, peptide length, net charge, and relative location of Fmoc and tryptophan on r1 and critical aggregation concentration (CAC) at 1.0 Tesla. Compared to nominal r1 values of 3.5-7.4 mM ^-1  s ^-1 per Gd(III), r1 values increased dramatically to 13.2-16.9 mM ^-1  s ^-1 per Gd(III) upon self-assembly, with CACs between 0.22 and 2.59 mM when tested in H2O or PBS. When tested in fetal bovine serum (FBS), the compounds maintained high r1 values of 11.2-13.0 mM ^-1  s ^-1 , but had dramatically lower CAC values below 25 μM. These findings guided the synthesis of two targeted, high-relaxivity MRI contrast agents that contained PSMA-binding ligand, DCL. Their r1 values in H2O or PBS increased from 5.9-7.4 mM ^-1  s ^-1 to 13.5-14.8 mM ^-1  s ^-1 with CAC values of 1.65-2.70 mM. In FBS, their r1 values were found to be 11.2-11.9 mM ^-1  s ^-1 , with CAC values below 25 μM. By the conjugation of targeting agents in the last step of synthesis, a broadly applicable route to targeted, high-relaxivity MRI contrast agents is offered.
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