title: Towards tropomyosin-related kinase B (TrkB) receptor ligands for brain imaging with PET: radiosynthesis and evaluation of 2-(4-[(18)F]fluorophenyl)-7,8-dihydroxy-4H-chromen-4-one and 2-(4-([N-methyl-(11)C]-dimethylamino)phenyl)-7,8-dihydroxy-4H-chromen-4-one.
abstract: The interaction of tropomyosin-related kinase B (TrkB) with the cognate ligand brain-derived neurotrophic factor (BDNF) mediates fundamental pathways in the development of the nervous system. TrkB signaling alterations are linked to numerous neurodegenerative diseases and conditions. Herein we report the synthesis, biological evaluation and radiosynthesis of the first TrkB radioligands based on the recently identified 7,8-dihydroxyflavone chemotype. 2-(4-[(18)F]fluorophenyl)-7,8-dihydroxy-4H-chromen-4-one ([(18)F]10b) was synthesized in high radiochemical yields via an efficient SNAr radiofluorination involving a para-Michael acceptor substituted aryl followed by BBr3-promoted double demethylation. Selective N-[(11)C]methylation afforded 2-(4-([N-methyl-(11)C]-dimethylamino)phenyl)-7,8-dihydroxy-4H-chromen-4-one ([(11)C]10c) from the fully deprotected catechol-bearing normethyl precursor 13 with [(11)C]MeOTf. In vitro autoradiography of [(18)F]10b with transverse rat brain sections revealed high specific binding in the cortex, striatum, hippocampus and thalamus in accordance with expected TrkB distribution. Blockade experiments with both 7,8-dihydroxyflavone (1a) and TrkB cognate ligand, BDNF, led to decreases of 80% and 85% of radioligand binding strongly supporting the hypothesis that 7,8-dihydroxyflavones exert their effect on TrkB phosphorylation via direct TrkB extracellular domain (ECD) binding. Positron emission tomography (PET) studies revealed that [(18)F]10b and [(11)C]10c brain uptake is minimal and that they are rapidly eliminated from the plasma (effective plasma half-life 5-10 min) via hepatic secretion. Nevertheless, the high specific binding and TrkB specificity derived from in vitro experiments suggests that the 7,8-disubstituted flavone chemotype represents a promising scaffold for the development of TrkB radiotracers for PET.
authors.affiliation: Department of Chemistry, Université de Montréal, PO Box 6128, Station Downtown, QC H3C 3J7, Canada; McConnell Brain Imaging Centre, Montreal Neurological Institute, McGill University, 3801 University Street, Montreal, QC H3A 2B4, Canada.
authors.forename: Vadim
authors.initials: V
authors.lastname: Bernard-Gauthier
authors.forename: Mehdi
authors.initials: M
authors.lastname: Boudjemeline
authors.forename: Pedro
authors.initials: P
authors.lastname: Rosa-Neto
authors.forename: Alexander
authors.initials: A
authors.lastname: Thiel
authors.forename: Ralf
authors.initials: R
authors.lastname: Schirrmacher
mesh_terms: D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging* / Q000378:metabolism; D018360:Crystallography, X-Ray; D047309:Flavones / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D020813:Receptor, trkB / Q000378:metabolism*
chemical_list: C000591639:2-(4-(dimethylamino)phenyl)-7,8-dihydroxy-4H-chromen-4-one; C000591638:2-(4-fluorophenyl)-7,8-dihydroxy-4H-chromen-4-one; D047309:Flavones; D008024:Ligands; D019275:Radiopharmaceuticals; D020813:Receptor, trkB
keywords: 7,8-Dihydroxyflavone; Carbon-11; Fluorine-18; Positron emission tomography; Radiochemistry; Tropomyosin-related kinases B receptor