The pro-psychotic metabotropic glutamate receptor compounds fenobam and AZD9272 share binding sites with monoamine oxidase-B inhibitors in humans

The metabotropic glutamate receptor 5 (mGluR5) has been a significant target for drug development in neuropsychiatric conditions, including depression and anxiety. Two specific drug candidates, fenobam and AZD9272, were developed as negative allosteric modulators (NAMs) of mGluR5. However, both were discontinued in early clinical trials due to the emergence of adverse, psychosis-like symptoms. Previous research noted that [11C]AZD9272 exhibited an unexpected, non-mGluR5-related binding pattern in the brain. Given that this pattern resembles the regional distribution of the enzyme monoamine oxidase-B (MAO-B), the researchers sought to determine if fenobam and AZD9272 actually bind to MAO-B.

The researchers re-evaluated PET scan data from human subjects to correlate the regional binding of [11C]AZD9272 with known mGluR5 (via [11C]ABP688) and MAO-B (via [11C]L-deprenyl-D2) radioligands. They further investigated this relationship through in vivo competition studies in non-human primates and in vitro autoradiography in human brain tissue, testing whether administration of known MAO-B inhibitors or mGluR5 ligands could displace the binding of AZD9272.

The PET imaging revealed a strong spatial correlation between [11C]AZD9272 and the MAO-B radioligand [11C]L-deprenyl-D2, but essentially no correlation with the mGluR5-specific ligand [11C]ABP688. Multilinear regression modeling indicated that mGluR5-specific binding accounted for only a minor fraction (5-20%) of the total [11C]AZD9272 signal. Competition studies confirmed these findings; MAO-B inhibitors potently displaced [18F]AZD9272 binding in the primate brain and human tissue samples. Conversely, the binding of the MAO-B radioligand was significantly inhibited by the addition of fenobam or AZD9272.