title: 11C-LY2428703, a positron emission tomographic radioligand for the metabotropic glutamate receptor 1, is unsuitable for imaging in monkey and human brains.
abstract: BACKGROUND
  A recent study from our laboratory demonstrated that 11C-LY2428703, a new positron emission tomographic radioligand for metabotropic glutamate receptor 1 (mGluR1), has promising in vitro properties and excellent in vivo performance for imaging rat brain. The present study evaluated 11C-LY2428703 for imaging mGluR1 in monkey and human brains.
  
  
  METHODS
  Rhesus monkeys were imaged at baseline and after administration of an mGluR1 blocking agent to calculate nonspecific binding, as well as after the administration of permeability glycoprotein (P-gp) and breast cancer resistance protein (BCRP) blockers to assess whether 11C-LY2428703 is a substrate for efflux transporters at the blood-brain barrier. Human imaging was performed at baseline in three healthy volunteers, and arterial input function was measured.
  
  
  RESULTS
  Overall brain uptake was low in monkeys, though slightly higher in the cerebellum, where mGluR1s are concentrated. However, the uptake was not clearly displaceable in the scans after mGluR1 blockade. Brain penetration of the ligand did not increase after P-gp and BCRP blockade. Brain uptake was similarly low in all human subjects (mean VT with a two-tissue compartment model, 0.093 ± 0.012 mL/cm3) and for all regions, including the cerebellum.
  
  
  CONCLUSIONS
  Despite promising in vitro and in vivo results in rodents, 11C-LY2428703 was unsuitable for imaging mGluR1s in monkey or human brain because of low brain uptake, which was likely caused by high binding to plasma proteins.
authors.affiliation: Molecular Imaging Branch, National Institute of Mental Health, 10 Center Drive, Bethesda, MD 20892, USA. innisr@mail.nih.gov.
authors.forename: Paolo
authors.initials: P
authors.lastname: Zanotti-Fregonara
authors.forename: Vanessa N
authors.initials: VN
authors.lastname: Barth
authors.forename: Sami S
authors.initials: SS
authors.lastname: Zoghbi
authors.forename: Jeih-San
authors.initials: JS
authors.lastname: Liow
authors.forename: Eric
authors.initials: E
authors.lastname: Nisenbaum
authors.forename: Edward
authors.initials: E
authors.lastname: Siuda
authors.forename: Robert L
authors.initials: RL
authors.lastname: Gladding
authors.forename: Denise
authors.initials: D
authors.lastname: Rallis-Frutos
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