Efficient radiosynthesis and preclinical evaluation of [ F]FOMPyD as a positron emission tomography tracer candidate for TrkB/C receptor imaging.

Herein we report an efficient radiolabeling of a F-fluorinated derivative of dual inhibitor GW2580, with its subsequent evaluation as a positron emission tomography (PET) tracer candidate for imaging of two neuroreceptor targets implicated in the pathophysiology of neurodegeneration: tropomyosin receptor kinases (TrkB/C) and colony stimulating factor receptor (CSF-1R). [ F]FOMPyD was synthesized from a boronic acid pinacolate precursor via copper-mediated F-fluorination concerted with thermal deprotection of the four Boc groups on a diaminopyrimidine moiety in an 8.7±2.8% radiochemical yield, a radiochemical purity >99%, and an effective molar activity of 187±93 GBq/μmol. [ F]FOMPyD showed moderate brain permeability in wild-type rats (SUV = 0.75) and a slow washout rate. The brain uptake was partially reduced (ΔAUC = 11.6%) by administration of the nonradioactive FOMPyD (up to 30 μg/kg). In autoradiography, [ F]FOMPyD exhibits ubiquitous distribution in rat and human brain tissues with relatively high nonspecific binding revealed by self-blocking experiment. The binding was blocked by TrkB/C inhibitors, but not with a CSF-1R inhibitor, suggesting selective binding to the former receptor. Although an unfavorable pharmacokinetic profile will likely preclude application of [ F]FOMPyD as a PET tracer for brain imaging, the concomitant one-pot copper-mediated F-fluorination/Boc-deprotection is a practical technique for the automated radiosynthesis of acid-sensitive PET tracers.