A modular synthesis of multi- or dual-metal targeted imaging agents for PET, SPECT and MRI has been developed. In the peptide-based approach, metals chelated to DOTA are placed on the side chains of amino acids early in the synthesis followed by coupling to modules, then to linkers and targeting agents in the last step, enabling the use of a variety of targeting systems for a given imaging system. The method can be applied to the synthesis of multi-gadolinium MRI agents for higher relaxivity, or to combine two different metals offering dual-modal PET/SPECT-MRI agents. It was first found that a metal introduced early can double as a protecting group for DOTA, averting the need for the common but troublesome tri-t-butyl protection. It was further discovered that two labile metals, La+3 or Ce+3, can used as placeholders, then transmetalated rapidly in mild acid by Cu+2, Ga+3, In+3 and Y+3. These masked PET agents can be shipped without encumbrance to clinical labs where radioactive metals for PET can be inserted rapidly in the final transmetalation in mild acid. Conditions for metal exchange were optimized in a kinetic study in dilute TFA. Gd+3 was found to be inert to exchange enabling synthesis of PET-MRI agents. The modular method was applied to the synthesis of single modal (MRI and PET) and dual modal (PET-MRI) targeted agents utilizing c(RGDyK) for lung cancer and urea DCL for prostate cancer.l

Practical modular synthesis of targeted imaging agents for MRI, PET and PET-MRI

256th National Meeting (2018)

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