Towards tropomyosin-related kinase B (TrkB) receptor ligands for brain imaging with PET: Radiosynthesis and evaluation of 2-(4-[18F]fluorophenyl)-7,8-dihydroxy-4H-chromen-4-one and 2-(4-([N-methyl-11C]-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-4 H -chromen-4-one ([ 18 F] 10b ) was synthesized in high radiochemical yields via an efficient S N Ar radiofluorination involving a para -Michael acceptor substituted aryl followed by BBr 3 -promoted double demethylation. Selective N-[ 11 C]methylation afforded 2-(4-([ N -methyl- 11 C]-dimethylamino)phenyl)-7,8-dihydroxy-4 H -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.