Document Detail

Evaluation in vitro and in animals of a new 11C-labeled PET radioligand for metabotropic glutamate receptors 1 in brain.
MedLine Citation:
PMID:  23135321     Owner:  NLM     Status:  MEDLINE    
PURPOSE: 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.
CONCLUSION: (11)C-LY2428703, a new PET radioligand for mGluR1 quantification, displayed promising characteristics both in vitro and in vivo in rodents.
Paolo Zanotti-Fregonara; Vanessa N Barth; Jeih-San Liow; Sami S Zoghbi; David T Clark; Emily Rhoads; Edward Siuda; Beverly A Heinz; Eric Nisenbaum; Bruce Dressman; Elizabeth Joshi; Debra Luffer-Atlas; Matthew J Fisher; John J Masters; Nancy Goebl; Steven L Kuklish; Cheryl Morse; Johannes Tauscher; Victor W Pike; Robert B Innis
Publication Detail:
Type:  In Vitro; Journal Article; Research Support, N.I.H., Intramural     Date:  2012-11-08
Journal Detail:
Title:  European journal of nuclear medicine and molecular imaging     Volume:  40     ISSN:  1619-7089     ISO Abbreviation:  Eur. J. Nucl. Med. Mol. Imaging     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2013-01-04     Completed Date:  2013-06-27     Revised Date:  2014-01-09    
Medline Journal Info:
Nlm Unique ID:  101140988     Medline TA:  Eur J Nucl Med Mol Imaging     Country:  Germany    
Other Details:
Languages:  eng     Pagination:  245-53     Citation Subset:  IM    
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MeSH Terms
Allosteric Site
Blood-Brain Barrier
Brain / pathology*
Carbon Isotopes / pharmacology*
Chromatography, Liquid / methods
Inhibitory Concentration 50
Mice, Knockout
Models, Chemical
Positron-Emission Tomography / methods*
Receptors, Metabotropic Glutamate / metabolism*
Spectrometry, Mass, Electrospray Ionization / methods
Tandem Mass Spectrometry / methods
Grant Support
Reg. No./Substance:
0/Carbon Isotopes; 0/Ligands; 0/Receptors, Metabotropic Glutamate

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