Abstract

The metabotropic glutamate receptor 5 (mGlu₅) is a recognized CNS therapeutic target for which several negative allosteric modulators (NAM) drug candidates have or are continuing to be investigated for various disease indications in clinical development. Direct measurement of target receptor occupancy (RO) is extremely useful to help design and interpret efficacy and safety in nonclinical and clinical studies. In the mGlu₅ field, this has been successfully achieved by monitoring displacement of radiolabeled ligands, specifically binding to the mGlu₅ receptor, in the presence of an mGlu₅ NAM using in vivo and ex vivo binding in rodents and positron emission tomography imaging in cynomolgus monkey and humans. The aim of this study was to measure the RO of the mGlu₅ NAM, HTL0014242, in rodents and cynomolgus monkey and to compare its plasma, and brain, exposure-RO relationships with those of clinically tested mGlu₅ NAMs dipraglurant, mavoglurant and basimglurant. Potential sources of variability that may contribute to these relationships were explored. Distinct plasma exposure-response relationships were found for each mGlu₅ NAM with >100-fold difference in plasma exposure for a given level of RO. However, a unified exposure-response relationship was observed when both unbound brain concentration and mGlu₅ affinity were considered. This relationship showed <10-fold overall difference, fitted with a Hill slope which was not significantly different from 1 and appeared consistent with a simple E_max model. This is the first time this type of comparison has been conducted, demonstrating a unified brain exposure-RO relationship across several species and mGlu₅ NAMs with diverse properties.

Significance Statement Despite the long history of mGlu₅ as a therapeutic target and progression of multiple compounds to the clinic, no formal comparison of exposure-receptor occupancy relationships has been conducted. Our data indicate for the first time that a consistent, unified relationship can be observed between exposure and mGlu₅ receptor occupancy when unbound brain concentration and receptor affinity are taken into account across a range of species for a diverse set of mGlu₅ NAMs, including a new drug candidate, HTL0014242.