Colony stimulating factor 1 receptor is a cell-surface class III tyrosine kinase receptor (CSF1R). In brain, CSF1R plays a pivotal role in regulating the development of microglia, the resident immune cells that are involved in neuroinflammation. Although activation of CSF1R promotes the survival and the proliferation of microglia, CSF1R overexpression is associated with several disorders. Positron emission tomography (PET) might be exploited with a suitably specific radioligand for non-invasively quantifying CSF1R levels in living human brains in biomedical research on neuropsychiatric disorders. Several CSF1R inhibitors have been described. Among them, the potent (IC50 = 3 nM) cinnoline-core type inhibitor 2 reported by AstraZeneca appeared to have very favorable physicochemical properties for development as a PET radiotracer, including molecular weight of 406 Da, TPSA of 76 Å, and clogD7.4 of 2.9. In addition, the presence of potential sites for labeling with carbon-11 (t1/2 = 20 min) or fluorine-18 (t1/2 = 110 min) prompted us to consider this inhibitor for development as a PET radiotracer for CSF1R imaging. The commercially available precursor 1 (2.5 µmol) was treated with [11C]MeI in DMF (0.4 mL) in the presence of TMP base (1.1 eq.) at 100 °C for 5 min to give [11C]2, which was purified with HPLC and formulated for intravenous injection. The whole radiosynthesis required 38 min. Evaluation of [11C]2 in non-human primates and rodents with PET showed negligible brain uptake (SUV = 0.2). Furthermore, [11C]2 appeared to be a weak substrate of the ATP-active efflux pumps at the blood-brain barrier. Therefore, [11C]2 is ineffective as a PET radiotracer for CSF1R.

Synthesis and evaluation of a cinnoline-core type candidate radiotracer for positron emission tomography of brain macrophage colony-stimulating factor 1 receptor

2019 Fall National Meeting

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