The serine/threonine protein kinase DNA-dependent protein kinase (DNA-PK) is an attractive target for cancer treatment and molecular imaging of cancer, since the ability of cancer cells to survive radiotherapy and chemotherapy is often due to their efficiency in repairing the DNA damage that these treatment elicit, and DNA-PK is a key enzyme involved in the repair of DNA double strand breaks (DSBs). Recently a new series of chromen-4-one derivatives has been developed by Griffin et al. as potent and selective inhibitors of DNA-PK to enhance the cytotoxicity of DNA-damaging therapies used in the treatment of cancer. New carbon-11-labeled chromen-4-one derivatives were first designed and synthesized as agents for biomedical imaging technique positron emission tomography (PET) to image DNA-PK in cancer. Unlabeled chromen-4-one derivatives, precursors X-hydroxy-2-morpholino-4H-chromen-4-ones (X=8,7,6,5) and standards X-methoxy-2-morpholino-4H-chromen-4-ones (X=8,7,6,5), were synthesized from 2-hydroxy-X-methoxybenzoic acids (X=3,4,5,6) in 4 and 3 steps with 20-40% and 36-50% overall chemical yield, respectively. The target tracers, X-[11C]methoxy-2-morpholino-4H-chromen-4-ones (X=8,7,6,5), were prepared from their corresponding precursors, X-hydroxy-2-morpholino-4H-chromen-4-ones (X=8,7,6,5), with [11C]CH3OTf through O-[11C]methylation and isolated by a simplified solid-phase extraction (SPE) method using a C-18 Sep-Pak Plus cartridge in 40-60% radiochemical yields, decay corrected to end of bombardment (EOB), based on [11C]CO2, with 185-370 GBq/�mol specific activity at end of synthesis (EOS).

Synthesis of carbon-11-labeled chromen-4-one derivatives as new potential PET agents for imaging of DNA-dependent protein kinase in cancer

243rd National Meeting (2012)

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