While combinatorial approaches have been used in the development of therapeutic agents for some time, seldom are they used for the development of imaging agents. In an initial study we apply combinatorial principles to molecular imaging tool developments by using on-bead combinations of peptoids and DOTA. Peptoids are a class of peptidomimetics closely related to peptides and are emerging as biologically amenable compounds with a very quick and cost effective synthesis and optimization. DOTA is one of the most applied contrast agents used in imaging. In the study which involved making peptoid modifications onto DOTA side arms, we evaluated various physio-chemical parameters affecting the metal-bound water exchange mechanism. We chose CEST imaging as the model system as the sensitivy of CEST-MRI agents is highly dependent on the rate of water exchange between the inner sphere of a paramagnetic ion and bulk water. Parameters such as electronic effects, hydrophobicity, polarity and sterics of the substituents attached to the DOTA side arms can affect this water exchange. We have developed rapid and economical on-bead library of 80 Eu(III) DOTA-tetra-amide peptoids using a variety of charged, uncharged polar, hydrophobic and sterically diverse peptoid moieties as substients. The whole library was imaged via usage of a 63 mm diameter quadrature volume coil of a 9.4 T animal imaging system. From the study, the CEST image of the library allowed describing the chemical features of a ligand that had most influence on water exchange rates. In a subsequent study, a focused library of 85 different Eu(III) DOTA tetra-amide substituted compounds directly identified the most improved CEST agent. This technique can further be readily adapted to other types of MRI or MR/PET agents as well.

Peptoid-combinatorial strategies for molecular imaging tool developments

247th National Meeting (2014)

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