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Synthesis 2019; 51(23): 4374-4384
DOI: 10.1055/s-0039-1690522
special topic
© Georg Thieme Verlag Stuttgart · New York

Preparation of the Serotonin Transporter PET Radiotracer 2-({2-[(Dimethylamino)methyl]phenyl}thio)-5-[18F]fluoroaniline (4-[18F]ADAM): Probing Synthetic and Radiosynthetic Methods

Selena Milicevic Sephton  ∗
Molecular Imaging Chemistry Laboratory, Wolfson Brain Imaging Centre, Department of Clinical Neurosciences, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0SZ, UK   Email: sms96@cam.ac.uk
,
Xiaoyun Zhou
,
Stephen Thompson 
,
Franklin I. Aigbirhio
› Author AffiliationsThis work was in part funded by an internal grant from the Behavioural and Clinical Neuroscience Institute (BCNI), University of Cambridge.
Further Information

Publication History

Received: 26 June 2019

Accepted after revision: 25 July 2019

Publication Date:
21 August 2019 (online)

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Published as part of the Special Topic Halogenation methods (with a view towards radioimaging applications)

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.

Key words

4-[18F]ADAM - serotonin transporter - copper-mediated fluorination - 18F-radiolabelling - PET imaging

Supporting Information

    Supporting information for this article is available online at https://doi.org/10.1055/s-0039-1690522.
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