Design and Synthesis of a 18F-Radiolabeled Pyrrolo[2,3-d]pyrimidine Ligand as a CSF1R Receptor PET Imaging Agent

Abstract

Colony-stimulating factor 1 receptor (CSF1R or c-FMS), a class III receptor tyrosine kinase, is significantly expressed in mononuclear phagocytes and in the central nervous system. It has been identified as a potential drug and imaging target in numerous inflammatory, cancerous, and neurodegenerative diseases. Despite several attempts, no validated CSF1R PET tracer is currently available. Herein, we report the design and synthesis of a ¹⁸F-radiolabeled pyrrolo[2,3-d]pyrimidine molecule based on previously developed potent and selective CSF1R inhibitors. Initially, a nonlabeled fluorinated compound was synthesized using conventional and microwave methods, and it exhibited potent CSF1R inhibitory activity (IC₅₀ = 6 nM). A tosylate precursor was then synthesized for subsequent radiofluorination. The ¹⁸F-radiolabeled compound was produced using K[¹⁸F]F Kryptofix 222 (K_2.2.2)-carbonate in acetonitrile (10% DMF). The optimal labeling conditions, with a tosylate leaving group at 100°C for 5 min, resulted in the production of the ¹⁸F-radiolabeled pyrrolo[2,3-d]pyrimidine CSF1R inhibitor with high purity and with a molar activity of the final product of 57 GBq/μmol. The synthesized inhibitor might open new possibilities for in vivo imaging in neuroinflammation and related disorders, and future studies will evaluate its performance as a PET tracer.