Synthesis of Radiotracers to Image Neuroinflammation in Alzheimer’s Disease

Alzheimer’s disease (AD) remains one of the most devastating neurodegenerative disorders, with 10 million new cases reported every year. Despite decades of research, its early and accurate diagnosis continues to pose a major clinical challenge, emphasizing the need for sensitive molecular imaging techniques. Positron emission tomography (PET) imaging, through the use of specific radiotracers, offers a powerful tool to visualize and quantify key molecular targets involved in the disease [1].
Among these targets, Monoamine Oxidase-B (MAO-B) has emerged as a promising biomarker for early AD detection, as it is massively upregulated during the neuroinflammatory phase occurring in the early stages of the disease [2]. [¹⁸F]SMBT-1, a well-established radiotracer for MAO-B [3], has proven to be a highly promising candidate, although its synthesis has so far remained difficult to achieve reliably. The overarching aim of this project is therefore to develop a robust, reliable, and straightforward automated radiosynthesis process suitable for routine clinical production of [¹⁸F]SMBT-1. Our first objective was to synthesize the non-radioactive SMBT-1, which served (i) to investigate protection and deprotection strategies and (ii) as an analytical reference for the development of QC methods and confirmation of the radiotracer’s identity. In a second step, the synthesis of the tosylated precursor was undertaken to enable the subsequent incorporation of radioactive fluorine-18. Initial radiolabelling experiments proved challenging, with radiochemical yields below 5%. Further investigation identified contamination with trace amounts of chloride and chlorinated analogues as a potential cause. To address this, alternative synthetic routes were explored, focusing on the reactivity of tosylated epoxides, allyl derivatives, and the various alcohol groups within the molecule.