Is There a Role for GPCR Agonist Radiotracers in PET Neuroimaging?

Abstract

Positron emission tomography (PET) is a molecular imaging modality that enables in vivo exploration of metabolic processes and especially the pharmacology of neuroreceptors. G protein-coupled receptors (GPCRs) play an important role in numerous pathophysiologic disorders of the central nervous system. Thus, they are targets of choice in PET imaging to bring proof concept of change in density in pathological conditions or in pharmacological challenge. At present, most radiotracers are antagonist ligands. In vitro data suggest that properties differ between GPCR agonists and antagonists: antagonists bind to receptors with a single affinity, whereas agonists are characterized by two different affinities: high affinity for receptors that undergo functional coupling to G-proteins, and low affinity for those that are not coupled. In this context, agonist radiotracers may be useful tools to give functional images of GPCRs in the brain, with high sensitivity to neurotransmitter release. Here, we review all existing PET radiotracers used from animals to humans and their role for understanding the ligand-receptor paradigm of GPCR in comparison with corresponding antagonist radiotracers.

Optimizing clozapine for chemogenetic neuromodulation of somatosensory cortex

“…However, we did not observe any increases in metabolic activity in somatosensory cortex with FDG-microPET imaging in this study, despite observing electrophysiological activation of DREADDs by CLZ in this area. We hypothesize that the metabolic deactivation we observed may be produced by special conditions related to the chemogenetic activation induced by CLZ: although GPCR signaling induced by DREADD stimulation evokes complex signaling cascades, interactions with various channels, and phosphorylation of diverse proteins 35 , the energy consumption of GPCR signaling is much lower than that of synaptic ion channels, which are the major consumer of energy in the brain 36 . Thus it is possible that this underlies the activation pattern observed with microPET imaging.…”

Neuronal Dopamine D3 Receptors: Translational Implications for Preclinical Research and CNS Disorders

“…Great efforts have been made to develop PET ligands (both agonists or antagonists) for in vivo imaging of D3Rs and D2Rs. Many of them displayed high affinity for both D2Rs and D3Rs, but either their selectivity or physicochemical properties or brain penetration were far from satisfactory [ 162 , 163 , 164 , 165 , 166 ] to differentiate between imaging of D2Rs and D3Rs. Availability of the high affinity and D3R preferring agonist [ 11 C]-(+)-PHNO [ 42 ] has made possible to image D3Rs in the human brain [ 44 , 167 ].…”

Towards in vivo imaging of functionally active 5-HT1A receptors in schizophrenia: concepts and challenges

“…The vast majority of PET radiopharmaceuticals currently used for receptor neuroimaging are antagonists. However, about 30 agonists have been used for PET imaging of various G-protein-coupled receptors: adrenergic, dopaminergic, serotonergic, muscarinic, cannabinoid, and opioid receptors [55][56][57] . Among them, a dozen of PET agonist radiotracers were developed and translated to humans for these receptors, but very few studies [58][59][60] directly compared the in vivo density of receptors targeted by an agonist versus an antagonist radiotracer in the same subject (in these cases, animal models).…”

“…The internalization of certain receptors has been evoked, as well as the modification of their allosteric conformations, or the influence of the extracellular concentration of the endogenous neurotransmitter, all of which could influence differently the binding of an antagonist and an agonist for the same family of receptors (see ref. 56 for a review on this subject).…”