title: Evaluation in vitro and in animals of a new 11C-labeled PET radioligand for metabotropic glutamate receptors 1 in brain.
abstract: OBJECTIVE
  Two allosteric modulators of the group I metabotropic glutamate receptors (mGluR1 and mGluR5) were evaluated as positron emission tomography (PET) radioligands for mGluR1.
  
  
  METHODS
  LY2428703, a full mGluR1 antagonist (IC(50) 8.9 nM) and partial mGluR5 antagonist (IC(50) 118 nM), and LSN2606428, a full mGluR1 and mGluR5 antagonist (IC(50) 35.3 nM and 10.2 nM, respectively) were successfully labeled with (11)C and evaluated as radioligands for mGluR1. The pharmacology of LY2428703 was comprehensively assessed in vitro and in vivo, and its biodistribution was investigated by liquid chromatography-mass spectrometry/mass spectrometry, and by PET imaging in the rat. In contrast, LSN2606428 was only evaluated in vitro; further evaluation was stopped due to its unfavorable pharmacological properties and binding affinity.
  
  
  RESULTS
  (11)C-LY2428703 showed promising characteristics, including: (1) high potency for binding to human mGluR1 (IC(50) 8.9 nM) with no significant affinity for other human mGlu receptors (mGluR2 through mGluR8); (2) binding to brain displaceable by administration of an mGluR1 antagonist; (3) only one major radiometabolite in both plasma and brain, with a negligible brain concentration (with 3.5 % of the total radioactivity in cerebellum) and no receptor affinity; (4) a large specific and displaceable signal in the mGluR1-rich cerebellum with no significant in vivo affinity for mGluR5, as shown by PET studies in rats; and (5) lack of substrate behavior for efflux transporters at the blood-brain barrier, as shown by PET studies conducted in wild-type and knockout mice.
  
  
  CONCLUSIONS
  (11)C-LY2428703, a new PET radioligand for mGluR1 quantification, displayed promising characteristics both in vitro and in vivo in rodents.
authors.affiliation: Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, 10 Center Drive, Bethesda, MD 20892, USA.
authors.forename: Paolo
authors.initials: P
authors.lastname: Zanotti-Fregonara
authors.forename: Vanessa N
authors.initials: VN
authors.lastname: Barth
authors.forename: Jeih-San
authors.initials: JS
authors.lastname: Liow
authors.forename: Sami S
authors.initials: SS
authors.lastname: Zoghbi
authors.forename: David T
authors.initials: DT
authors.lastname: Clark
authors.forename: Emily
authors.initials: E
authors.lastname: Rhoads
authors.forename: Edward
authors.initials: E
authors.lastname: Siuda
authors.forename: Beverly A
authors.initials: BA
authors.lastname: Heinz
authors.forename: Eric
authors.initials: E
authors.lastname: Nisenbaum
authors.forename: Bruce
authors.initials: B
authors.lastname: Dressman
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Joshi
authors.forename: Debra
authors.initials: D
authors.lastname: Luffer-Atlas
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Fisher
authors.forename: John J
authors.initials: JJ
authors.lastname: Masters
authors.forename: Nancy
authors.initials: N
authors.lastname: Goebl
authors.forename: Steven L
authors.initials: SL
authors.lastname: Kuklish
authors.forename: Cheryl
authors.initials: C
authors.lastname: Morse
authors.forename: Johannes
authors.initials: J
authors.lastname: Tauscher
authors.forename: Victor W
authors.initials: VW
authors.lastname: Pike
authors.forename: Robert B
authors.initials: RB
authors.lastname: Innis
mesh_terms: D000495:Allosteric Site; D000818:Animals; D001812:Blood-Brain Barrier; D001921:Brain / Q000473:pathology*; D002247:Carbon Isotopes / Q000494:pharmacology*; D002853:Chromatography, Liquid / Q000379:methods; D006801:Humans; D066298:In Vitro Techniques; D020128:Inhibitory Concentration 50; D008024:Ligands; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008956:Models, Chemical; D049268:Positron-Emission Tomography / Q000379:methods*; D051381:Rats; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism*; D021241:Spectrometry, Mass, Electrospray Ionization / Q000379:methods; D053719:Tandem Mass Spectrometry / Q000379:methods
chemical_list: D002247:Carbon Isotopes; D008024:Ligands; D018094:Receptors, Metabotropic Glutamate