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J Labelled Comp Radiopharm. 2020 Jan 9. doi: 10.1002/jlcr.3827. [Epub ahead of print]

Efficient radiosynthesis and preclinical evaluation of [18 F]FOMPyD as a PET tracer candidate for TrkB/C receptor imaging.

Author information

1
McConnell Brain Imaging Centre, Montreal Neurological Institute, McGill University, Montreal, QC, Canada.
2
Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada.
3
Department of Oncology, Division of Oncological Imaging, University of Alberta, Edmonton, AB, Canada.
4
Translational Neuroimaging Laboratory, McGill Centre for Studies in Aging, Douglas Mental Health University Institute, Montreal, QC, Canada.

Abstract

Herein we report an efficient radiolabeling of a 18 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). [18 F]FOMPyD was synthesized from a boronic acid pinacolate precursor via copper-mediated 18 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. [18 F]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 non-radioactive FOMPyD (up to 30 μg/kg). In autoradiography, [18 F]FOMPyD exhibits ubiquitous distribution in rat and human brain tissues with relatively high non-specific 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 [18 F]FOMPyD as a PET tracer for brain imaging, the concomitant one-pot copper-mediated 18 F-fluorination/Boc-deprotection is a practical technique for the automated radiosynthesis of acid-sensitive PET tracers.

KEYWORDS:

Brain imaging; GW2580; PET; [18F]FOMPyD; colony stimulating factor receptor (CSF-1R); copper-mediated 18F-fluorination; fluorine-18; positron emission tomography; tropomyosin receptor kinase (Trk)

PMID:
31919878
DOI:
10.1002/jlcr.3827

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