Fluorinated pyrimidine 5-carboxamides as potential tools for MERTK targeted fluorine-18-PET-radioligand development

Area of Science:

• Neuroscience
• Radiochemistry
• Immunology

Background:

• Microglia play a crucial role in neuroprotection and repair, particularly in conditions like multiple sclerosis (MS).
• MER tyrosine kinase (MERTK) is a key marker for the anti-inflammatory and immunosuppressive phenotype of microglia.
• Developing imaging tools to differentiate microglial responses is vital for MS diagnosis and management.

Purpose of the Study:

• To discover novel ¹⁸F-radiotracers for imaging the protective microglial phenotype in MS.
• To identify potent and selective MERTK ligands for positron emission tomography (PET) tracer development.

Main Methods:

• Synthesis of fluorinated pyrimidine-5-carboxamide derivatives based on MERTK ligands.
• Evaluation of MERTK inhibitory potency using cell-based assays.
• Assessment of selectivity against off-target kinases like AXL, TYRO3, and FLT3.

Main Results:

• Discovery of several potent and selective fluorinated MERTK ligands.
• Compounds demonstrated promising inhibitory activity in cell-based assays relevant to *in vivo* imaging.
• Achieved selectivity over key off-target kinases, reducing potential confounding signals.

Conclusions:

• The identified compounds are promising candidates for developing novel PET tracers.
• These tracers could enable non-invasive imaging of the protective microglial phenotype in MS patients.
• This research paves the way for improved early detection and monitoring of MS progression and treatment response.