Radiolabeled CyclosaligenylMonophosphates of 5-Iodo-2′-deoxyuridine,5-Iodo-3′-fluoro-2′,3′-dideoxyuridine, and 3′-Fluorothymidinefor Molecular Radiotherapy of Cancer: Synthesis and Biological Evaluation

Targeted molecular radiotherapy opens unprecedented opportunitiesto eradicate cancer cells with minimal irradiation of normal tissues.Described in this study are radioactive cyclosaligenyl monophosphatesdesigned to deliver lethal doses of radiation to cancer cells. Thesecompounds can be radiolabeled with SPECT- and PET-compatible radionuclidesas well as radionuclides suitable for Auger electron therapies. Thischaracteristic provides an avenue for the personalized and comprehensivetreatment strategy that comprises diagnostic imaging to identify sitesof disease, followed by the targeted molecular radiotherapy basedon the imaging results. The developed radiosynthetic methods produceno-carrier-added products with high radiochemical yield and purity.The interaction of these compounds with their target, butyrylcholinesterase,depends on the stereochemistry around the P atom. IC50valuesare in the nanomolar range. In vitro studies indicate that radiationdoses delivered to the cell nucleus are sufficient to kill cells ofseveral difficult to treat malignancies including glioblastoma andovarian and colorectal cancers. [ABSTRACT FROM AUTHOR]