Oral Presentation 11th Annual Conference of the International Chemical Biology Society 2022

Design and Synthesis of Novel CNS Penetrant 18F Radiotracers of MERTK for the Imaging of Multiple Sclerosis (#34)

Lian LX Xue 1 , Jonathan JBB Baell 1 , Ramesh RM Mudududdla 1 , Trevor TK Kilpatrick 2 , Michele MB Binder 2 , Siu Wai SWW Wang 1 , Lucy LV Vivash 1 , Uwe UA Ackermann 3
  1. Monash University, Melbourne, VICTORIA, Australia
  2. Florey Institute of Neuroscience and Mental Health, Melbourne, VIctoria, Australia
  3. University of Melbourne, Melbourne, VIctoria, Australia

Positron emitting tomography (PET) imaging has emerged as a promising non-invasive technique for pathological studies due to its ability to accurately quantify specific biochemical processes in living organisms. However, its development in CNS diseases remains limited. Our project aims to design and synthesise PET radiotracers as imaging tools for the research into the pathology of multiple sclerosis (MS) as an example for future PET studies on CNS diseases. The selection of a representative imaging biomarker represents the first challenge of PET application to MS and other CNS diseases due to the limited understanding of the complicated pathologies. Here we propose MER tyrosine kinase (MERTK) as our biomarker, the upregulation of which is exclusively associated with M2 polarisation of microglia, featuring a reparative process of MS. Compared with other current MS biomarkers such as the translocator protein (TSPO), MERTK allows differential imaging between the pathogenic progression (M1) and reparative process (M2) of MS. In 2021, our group published the radiotracer [18F]MIPS15692, which, for the first time, provided proof-of-concept evidence in imaging MERTK expression in MS. Apart from excellent MERTK affinity (IC50 = 4.0 nM), the in vitro autoradiography study showed a high level of specific binding of [18F]MIPS15692 to MERTK in corpus callosum/hippocampus (CC/HC) regions of demyelinated mice, colocalising with the known areas of increased MERTK expression in this model. However, no in vivo PET image was discernible due to the low CNS penetration of this tracer. This issue represents another common obstacle in the development of CNS tracers – that is, the unique blood-brain barrier (BBB) requires special design of the radiotracers to be able to penetrate. Here we describe our second-generation candidate MIPS50669, which showed 30-fold higher CNS penetration in mice with even better MERTK affinity (IC50 = 2.4 nM) compared with MIPS15692. While more in vivo studies are underway, this study will provide significant insights for the radiotracer development of MS and other CNS diseases in the future.

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