| Alzheimer's Disease (AD) is the most prevalent form of dementia, accounting for a significant disease burden on a global scale. Despite its ubiquity, disease etiology, diagnosis, and treatment for AD still pose significant questions and issues for the scientific and medical communities. In one prominent disease theory, the 'metal hypothesis of AD,' the formation and elongation of amyloid beta plaques are promoted by interactions with metal ions in central nervous system tissue, including Cu and Zn. Small molecule metal chelators have been demonstrated to disrupt these metal-protein interactions, and show potential as AD therapeutic and diagnostic agents. The first positron emission tomography (PET) radiotracer designed to probe the metal hypothesis of AD, [18F]CABS13, was recently developed by the Vasdev group. The goal of this work was to prepare a 3-fluoro analog of [18F]CABS13 with the intent of improving upon its metabolic properties in vivo. The radiolabeling precursor, containing an iodonium (III) ylide leaving group, was targeted to be synthesized from 3-bromo-8-hydroxyquinoline. After derivatizing the 8-hydroxy group with a benzyl or benzyloxymethyl protecting group, bromine was substituted at the 3-position by a tributylstannyl group using a Stille reaction, followed by substitution with iodine. In ongoing studies, the iodine will be oxidized and converted to the spirocyclic or adamantyl based iodonium ylide precursor, which will be prepared for radiofluorination with 18F-labeled fluoride and deprotected for in vivo PET imaging studies. |
