PMID- 24183588
OWN - NLM
STAT- MEDLINE
DCOM- 20140922
LR  - 20161128
IS  - 1464-3391 (Electronic)
IS  - 0968-0896 (Linking)
VI  - 21
IP  - 24
DP  - 2013 Dec 15
TI  - 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.
PG  - 7816-29
LID - S0968-0896(13)00877-8 [pii]
LID - 10.1016/j.bmc.2013.10.012 [doi]
AB  - 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.
CI  - Copyright (c) 2013 Elsevier Ltd. All rights reserved.
FAU - Bernard-Gauthier, Vadim
AU  - Bernard-Gauthier V
AD  - Department of Chemistry, Universite de Montreal, 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.
FAU - Boudjemeline, Mehdi
AU  - Boudjemeline M
FAU - Rosa-Neto, Pedro
AU  - Rosa-Neto P
FAU - Thiel, Alexander
AU  - Thiel A
FAU - Schirrmacher, Ralf
AU  - Schirrmacher R
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20131019
PL  - England
TA  - Bioorg Med Chem
JT  - Bioorganic & medicinal chemistry
JID - 9413298
RN  - 0 (2-(4-(dimethylamino)phenyl)-7,8-dihydroxy-4H-chromen-4-one)
RN  - 0 (2-(4-fluorophenyl)-7,8-dihydroxy-4H-chromen-4-one)
RN  - 0 (Flavones)
RN  - 0 (Ligands)
RN  - 0 (Radiopharmaceuticals)
RN  - EC 2.7.10.1 (Receptor, trkB)
SB  - IM
MH  - Animals
MH  - Brain/*diagnostic imaging/metabolism
MH  - Crystallography, X-Ray
MH  - *Flavones/chemical synthesis/chemistry/pharmacokinetics
MH  - Ligands
MH  - Models, Molecular
MH  - Molecular Structure
MH  - *Positron-Emission Tomography
MH  - *Radiopharmaceuticals/chemical synthesis/chemistry/pharmacokinetics
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Receptor, trkB/*metabolism
OTO - NOTNLM
OT  - 7,8-Dihydroxyflavone
OT  - Carbon-11
OT  - Fluorine-18
OT  - Positron emission tomography
OT  - Radiochemistry
OT  - Tropomyosin-related kinases B receptor
EDAT- 2013/11/05 06:00
MHDA- 2014/09/23 06:00
CRDT- 2013/11/05 06:00
PHST- 2013/08/21 00:00 [received]
PHST- 2013/10/01 00:00 [revised]
PHST- 2013/10/10 00:00 [accepted]
PHST- 2013/11/05 06:00 [entrez]
PHST- 2013/11/05 06:00 [pubmed]
PHST- 2014/09/23 06:00 [medline]
AID - S0968-0896(13)00877-8 [pii]
AID - 10.1016/j.bmc.2013.10.012 [doi]
PST - ppublish
SO  - Bioorg Med Chem. 2013 Dec 15;21(24):7816-29. doi: 10.1016/j.bmc.2013.10.012. Epub 
      2013 Oct 19.