Compact, stabilized peptides have advantages in bioavailability and tissue penetration when utilized as scaffolds for imaging agents used in MRI, PET and optical imaging. The aim was to assemble these through a modular method in which imaging agents are pre-attached to the side chains of lysines, then coupled together, followed by conjugating to linkers and targeting groups. The result is a method for selectively combining two different dyes, or two metals, or mixing dyes with metals to create dual-dye, dual-metal, or dual-modal targeted imaging agents. Also via this route, a variety of targeting groups can be conjugated to a given imaging system in the final steps of synthesis. In an enabling discovery, it was found that a metal introduced early can serve as a protecting group for the chelator DOTA, allowing synthesis of high-relaxivity di-Gd MRI agents, or dual modal metal-dye agents for MRI-OMI. It was further discovered that lanthanides La or Ce may be used as place-holders in DOTA, and readily transmetalated in mild acid by Cu, In, Y, or Ga used in PET in the last step. Conversely, Gd was stable, thus yielding a route to targeted PET-MRI agents in which the final radioactive metal can be introduced easily in the clinic. A variety of single modal agents, and dual-modal agents for OMI-MRI and PET-MRI were synthesized utilizing RGDyK for targeting lung cancer, and the PSMA inhibitor DCL for targeting prostate cancer. Selective targeting of cancer cells was verified by in-vitro imaging with confocal fluorescence microscopy.

Modular synthesis of peptide-based single and multimodal targeted molecular imaging agents

256th National Meeting (2018)

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