title: 5-(4-((4-[(18)F]Fluorobenzyl)oxy)-3-methoxybenzyl)pyrimidine-2,4-diamine: a selective dual inhibitor for potential PET imaging of Trk/CSF-1R.
abstract: The tropomyosin receptor kinases (TrkA/B/C) and colony-stimulating factor-1 receptor (CSF-1R) represent highly pursued oncological therapeutic targets. The 2,4-diaminopyrimidine inhibitor GW2580 (9) has been previously reported as a highly selective low nanomolar TrkB/TrkC/CSF-1R inhibitor. In this study, fluorinated derivatives of 9 were designed, synthesized and evaluated in enzymatic assays. The highly potent inhibitor 10 was identified, which retained the selectivity profile of the non fluorinated lead compound 9, and the radiosynthesis of [(18)F]10 was developed. The results obtained from the biological evaluation of 10 and the radiosynthesis of [(18)F]10 support further investigation of this tracer as a potential PET imaging probe for TrkB/TrkC and CSF-1R.
authors.affiliation: Experimental Medicine, Department of Medicine, McGill University, 1110 Pine Avenue West, Montreal, QC H3A 1A3, Canada; Department of Oncology, University of Alberta, 11560 University Avenue, Edmonton, AB T6G 1Z2, Canada.
authors.forename: Vadim
authors.initials: V
authors.lastname: Bernard-Gauthier
authors.affiliation: Department of Oncology, University of Alberta, 11560 University Avenue, Edmonton, AB T6G 1Z2, Canada; McConnell Brain Imaging Centre, Montreal Neurological Institute, McGill University, 3801 University Street, Montreal, QC H3A 2B4, Canada. Electronic address: schirrma@ualberta.ca.
authors.forename: Ralf
authors.initials: R
authors.lastname: Schirrmacher
mesh_terms: D018360:Crystallography, X-Ray; D003959:Diamines / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005462:Fluorine Radioisotopes / Q000737:chemistry; D008958:Models, Molecular; D015394:Molecular Structure; D049268:Positron-Emission Tomography / Q000379:methods*; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology*; D019275:Radiopharmaceuticals / Q000737:chemistry / Q000494:pharmacology*; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020813:Receptor, trkB / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020812:Receptor, trkC / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: C000596289:5-(4-((4-fluorobenzyl)oxy)-3-methoxybenzyl)pyrimidine-2,4-diamine; D003959:Diamines; D005462:Fluorine Radioisotopes; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D019275:Radiopharmaceuticals; D016186:Receptor, Macrophage Colony-Stimulating Factor; D020813:Receptor, trkB; D020812:Receptor, trkC
keywords: Colony-stimulating factor 1 receptor; Diaminopyrimidine; Fluorine-18; GW2580; Radiochemistry; Tropomyosin receptor kinases; Tyrosine kinase inhibitor