Affiliation:
1. Molecular Imaging Chemistry Laboratory, Wolfson Brain Imaging Centre, Department of Clinical Neurosciences, University of Cambridge, Cambridge Biomedical Campus
Abstract
Serotonin transporters (SERTs) are involved in regulating the concentration of synaptic serotonin and present a good target for many neurologic and psychiatric disorder drugs. Positron-emission tomography (PET) is a valuable tool in both diagnosis and monitoring treatment therapies, and hence much effort is being given to developing suitable PET agents for imaging SERT. Our interest in applying the fluorine-18 analogue 4-[18F]ADAM for imaging SERT prompted the development of an improved synthetic route to access unlabelled ADAM. This is achieved using Pd-catalysed coupling with thiosalicylic acid and an EDC/HOBt amide coupling in 36% yield over 4 steps. A novel radiolabelling precursor, the pinacol-derived boronic ester, is prepared from the bromide using the Miyaura borylation and is obtained in 27% yield over 6 steps. Pinacolate is then used for the radiolabelling of 4-[18F]ADAM based on Cu-mediated nucleophilic fluorination in which the presence of oxygen is critical for the reaction. A 1:1 substrate to copper ratio is found to be optimal when the reaction is performed in dimethylacetamide at 85 °C. Using these conditions, 4-[18F]ADAM is prepared in 29 ± 10% (n = 6) radiochemical conversion after hydrolysis of the Boc group with HCl. Furthermore, the method is successfully automated to afford 4-[18F]ADAM in 10% radiochemical conversion.
Subject
Organic Chemistry,Catalysis
Cited by
2 articles.
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