Evaluation in vitro and in animals of a new ^sup 11^C-labeled PET radioligand for metabotropic glutamate receptors 1 in brain

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 (IC^sub 50^ 8.9 nM) and partial mGluR5 antagonist (IC^sub 50^ 118 nM), and LSN2606428, a full mGluR1 and mGluR5 antagonist (IC^sub 50^ 35.3 nM and 10.2 nM, respectively) were successfully labeled with ^sup 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. ^sup 11^C-LY2428703 showed promising characteristics, including: 1. high potency for binding to human mGluR1 (IC^sub 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. ^sup 11^C-LY2428703, a new PET radioligand for mGluR1 quantification, displayed promising characteristics both in vitro and in vivo in rodents.[PUBLICATION ABSTRACT]