Protein disulfide isomerase (PDI) is an enzyme primarily involved in protein folding diseases including neurological disorders and cancers. PDI is considered a potential drug target, and recently a novel series of small-molecule PDI inhibitors, substituted �-tetrahydrocarbolines, has been developed. PDI has become an attractive target for biomarkers for diagnostic in vivo imaging agents. Here we report the first design and synthesis of radiolabeled PDI inhibitors as new potential imaging agents for biomedical imaging technique positron emission tomography (PET) to image PDI. Unlabeled substituted �-tetrahydrocarboline precursors and reference standards were synthesized from tryptamine and a-ketoester in 2 steps with moderate to excellent yields. Carbon-11-labeled substituted �-tetrahydrocarbolines were prepared from their corresponding phenolic hydroxyl precursors with [11C]CH3OTf through O-[11C]methylation and isolated by simplified SPE in 50-60% decay corrected radiochemical yields from [11C]CO2 at EOB with 185-370 GBq/�mol specific activity at EOS. A fluorine-18-labeled substituted �-tetrahydrocarboline was prepared from its corresponding halo-precursors (X = Cl, Br, I) by the nucleophilic substitution with K[18F]F/Kryptofix 2.2.2 and isolated by HPLC combined with SPE purification in 25-40% decay corrected radiochemical yield from [18F]fluoride with 37-222 GBq/�mol specific activity at EOB.

Synthesis of radiolabeled protein disulfide isomerase (PDI) inhibitors as new potential PET agents for imaging of the enzyme PDI in neurological disorders and cancer

245th National Meeting (2013)

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