Efficient radiosynthesis and preclinical evaluation of [18F]FOMPyD as a positron emission tomography tracer candidate for TrkB/C receptor imaging |
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Authors: | Thomas A. Singleton Hussein Bdair Justin J. Bailey Sangho Choi Arturo Aliaga Pedro Rosa-Neto Ralf Schirrmacher Vadim Bernard-Gauthier Alexey Kostikov |
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Affiliation: | 1. McConnell Brain Imaging Centre, Montreal Neurological Institute, McGill University, Quebec, Canada;2. Department of Oncology, Division of Oncological Imaging, University of Alberta, Edmonton, Alberta, Canada;3. Translational Neuroimaging Laboratory, McGill Centre for Studies in Aging, Douglas Mental Health University Institute, Quebec, Canada |
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Abstract: | Herein we report an efficient radiolabeling of a 18F-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). [18F]FOMPyD was synthesized from a boronic acid pinacolate precursor via copper-mediated 18F-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. [18F]FOMPyD showed moderate brain permeability in wild-type rats (SUVmax = 0.75) and a slow washout rate. The brain uptake was partially reduced (ΔAUC40–90 = 11.6%) by administration of the nonradioactive FOMPyD (up to 30 μg/kg). In autoradiography, [18F]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 [18F]FOMPyD as a PET tracer for brain imaging, the concomitant one-pot copper-mediated 18F-fluorination/Boc-deprotection is a practical technique for the automated radiosynthesis of acid-sensitive PET tracers. |
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Keywords: | [18F]FOMPyD brain imaging colony stimulating factor receptor (CSF-1R) copper-mediated 18F-fluorination fluorine-18 GW2580 PET positron emission tomography tropomyosin receptor kinase (Trk) |
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