Imaging the 5-HT receptor with PET: Evaluation of 5-HT and 5-HT affinity of pimavanserin in the primate brain.

Two complimentary techniques were used to estimate occupancy of pimavanserin (a selective 5-HT inverse agonist) to 5-HT and 5-HT receptors in non-human primate brains. One employed the 5-HT selective radioligand [C]CIMBI-36 combined with quantification of binding potentials in brain regions known to be enriched in 5-HT (cortex) or 5-HT (choroid plexus) receptors to estimate occupancy. Pimavanserin was 6-10 fold more potent displacing [C]CIMBI-36 from cortex (ED = 0.

An evaluation of the brain distribution of [(11)C]GSK1034702, a muscarinic-1 (M 1) positive allosteric modulator in the living human brain using positron emission tomography.

Background: The ability to quantify the capacity of a central nervous system (CNS) drug to cross the human blood-brain barrier (BBB) provides valuable information for de-risking drug development of new molecules. Here, we present a study, where a suitable positron emission tomography (PET) ligand was not available for the evaluation of a potent muscarinic acetylcholine receptor type-1 (M1) allosteric agonist (GSK1034702) in the primate and human brain. Hence, direct radiolabelling of the novel molecule was performed and PET measurements were obtained and combined with in vitro equilibrium dialysis assays to enable assessment of BBB transport and estimation of the free brain concentration of GSK1034702 in vivo.

Relationship between glycine transporter 1 inhibition as measured with positron emission tomography and changes in cognitive performances in nonhuman primates.

Several lines of evidence suggest that schizophrenia is associated with deficits in glutamatergic transmission at the N-methyl-d-aspartate (NMDA) receptors. Glycine is a NMDA receptor co-agonist, and extracellular levels of glycine are regulated in the forebrain by the glycine type-1 transporters (GlyT-1). GlyT-1 inhibitors elevate extracellular glycine and thus potentiate NMDA transmission.

Characterising the plasma-target occupancy relationship of the neurokinin antagonist GSK1144814 with PET.

GSK1144814 is a potent, insurmountable antagonist at human NK₁ and NK₃ receptors. Understanding the relationship between plasma pharmacokinetics and receptor occupancy in the human brain, was crucial for dose selection in future clinical studies. GSK1144814 occupancy data were acquired in parallel with the first-time-in-human safety and tolerability study.

Imaging nicotine- and amphetamine-induced dopamine release in rhesus monkeys with [(11)C]PHNO vs [(11)C]raclopride PET.

The radiotracer [(11)C]PHNO may have advantages over other dopamine (DA) D2/D3 receptor ligands because, as an agonist, it measures high-affinity, functionally active D2/D3 receptors, whereas the traditionally used radiotracer [(11)C]raclopride measures both high- and low-affinity receptors. Our aim was to take advantage of the strength of [(11)C]PHNO for measuring the small DA signal induced by nicotine, which has been difficult to measure in preclinical and clinical neuroimaging studies. Nicotine- and amphetamine-induced DA release in non-human primates was measured with [(11)C]PHNO and [(11)C]raclopride positron emission tomography (PET) imaging.