Self‐Assembling Peptide‐Based High‐Relaxivity Targeted MRI Contrast Agents

Abstract 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.