Heterotrimeric guanine nucleotide–binding protein (G protein)–coupled receptors (GPCRs) can form multiprotein complexes (heteromers), which can alter the pharmacology and functions of the constituent receptors. Previous findings demonstrated that the Gq/11-coupled serotonin 5-HT2A receptor and the Gi/o-coupled metabotropic glutamate 2 (mGlu2) receptor—GPCRs that are involved in signaling alterations associated with psychosis—assemble into a heteromeric complex in the mammalian brain. In single-cell experiments with various mutant versions of the mGlu2 receptor, we showed that stimulation of cells expressing mGlu2–5-HT2A heteromers with an mGlu2 agonist led to activation of Gq/11 proteins by the 5-HT2A receptors. For this crosstalk to occur, one of the mGlu2 subunits had to couple to Gi/o proteins, and we determined the relative location of the Gi/o-contacting subunit within the mGlu2 homodimer of the heteromeric complex. Additionally, mGlu2-dependent activation of Gq/11, but not Gi/o, was reduced in the frontal cortex of 5-HT2A knockout mice and was reduced in the frontal cortex of postmortem brains from schizophrenic patients. These findings offer structural insights into this important target in molecular psychiatry.
Mutant
huntingtin (mHTT) protein carrying the elongated N-terminal
polyglutamine (polyQ) tract misfolds and forms protein aggregates
characteristic of Huntington’s disease (HD) pathology. A high-affinity
ligand specific for mHTT aggregates could serve as a positron emission
tomography (PET) imaging biomarker for HD therapeutic development
and disease progression. To identify such compounds with binding affinity
for polyQ aggregates, we embarked on systematic structural activity
studies; lead optimization of aggregate-binding affinity, unbound
fractions in brain, permeability, and low efflux culminated in the
discovery of compound 1, which exhibited target engagement
in autoradiography (ARG) studies in brain slices from HD mouse models
and postmortem human HD samples. PET imaging studies with 11C-labeled 1 in both HD mice and WT nonhuman primates
(NHPs) demonstrated that the right-hand-side labeled ligand [11C]-1R (CHDI-180R) is a suitable PET tracer for
imaging of mHTT aggregates. [11C]-1R is now
being advanced to human trials as a first-in-class HD PET radiotracer.
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