Distribution of [11C]-JNJ-42491293 in the marmoset brain: a positron emission tomography study

Abstract

JNJ-42491293 is a metabotropic glutamate 2 (mGlu₂) positive allosteric modulator (PAM) that was radiolabelled with [¹¹C]- to serve as a positron emission tomography (PET) ligand. Indeed, in vitro, the molecule displays high selectivity at mGlu₂ receptors. However, PET experiments performed in rats, macaques and humans, have suggested that [¹¹C]-JNJ-42491293 could interact with an unidentified, non-mGlu₂ receptor binding site. The brain distribution of [¹¹C]-JNJ-42491293 has not been determined in the brain of the common marmoset, a small non-human primate increasingly used in neuroscience research. Here, we investigated the distribution of [¹¹C]-JNJ-42491293 in the marmoset brain. Three marmosets underwent brain magnetic resonance imaging (MRI) and 90-min dynamic PET scans with [¹¹C]-JNJ-42491293 in combination with vehicle or the mGlu₂ PAM AZD8529 (0.1, 1 and 10 mg/kg). In the scans in which [¹¹C]-JNJ-42491293 was co-administered with vehicle, the brain areas with the highest standardised uptake values (SUVs) were the midbrain, cerebellum and thalamus, while the lowest SUVs were found in the pons. The addition of AZD8529 (0.1, 1 and 10 mg/kg) to [¹¹C]-JNJ-42491293 did not modify the SUVs obtained with [¹¹C]-JNJ-42491293 alone, and ex vivo blocking autoradiography with PAM AZD8529 (10, 100, 300 µM) on marmoset brain sections showed increased signals in the blocking conditions compared to vehicle, suggesting that no competition occurred between the 2 ligands. The results we obtained here do not suggest that [¹¹C]-JNJ-42491293 interacts selectively, or even at all, with mGlu₂ receptors in the marmoset, in agreement with findings previously reported in macaque and human.

Keywords: AZD8529; Marmoset; PET; Positive allosteric modulator; [11C]-JNJ-42491293; mGlu2 receptor.