期刊
EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING
卷 40, 期 2, 页码 245-253出版社
SPRINGER
DOI: 10.1007/s00259-012-2269-7
关键词
mGlu1 receptors; PET; Brain
资金
- Intramural Research Program of the National Institute of Mental Health, National Institutes of Health (IRP-NIMH-NIH)
Two allosteric modulators of the group I metabotropic glutamate receptors (mGluR1 and mGluR5) were evaluated as positron emission tomography (PET) radioligands for mGluR1. LY2428703, a full mGluR1 antagonist (IC50 8.9 nM) and partial mGluR5 antagonist (IC50 118 nM), and LSN2606428, a full mGluR1 and mGluR5 antagonist (IC50 35.3 nM and 10.2 nM, respectively) were successfully labeled with C-11 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. C-11-LY2428703 showed promising characteristics, including: (1) high potency for binding to human mGluR1 (IC50 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. C-11-LY2428703, a new PET radioligand for mGluR1 quantification, displayed promising characteristics both in vitro and in vivo in rodents.
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