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

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 (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 ¹¹C 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: ¹¹C-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. Conclusion: ¹¹C-LY2428703, a new PET radioligand for mGluR1 quantification, displayed promising characteristics both in vitro and in vivo in rodents.