Imaging of opioid receptors in the central nervous system

Abstract

In vivo functional imaging by means of positron emission tomography (PET) is the sole method for providing a quantitative measurement of mu-, kappa and delta-opioid receptor-mediated signalling in the central nervous system. During the last two decades, measurements of changes to the regional brain opioidergic neuronal activation--mediated by endogenously produced opioid peptides, or exogenously administered opioid drugs--have been conducted in numerous chronic pain conditions, in epilepsy, as well as by stimulant- and opioidergic drugs. Although several PET-tracers have been used clinically for depiction and quantification of the opioid receptors changes, the underlying mechanisms for regulation of changes to the availability of opioid receptors are still unclear. After a presentation of the general signalling mechanisms of the opioid receptor system relevant for PET, a critical survey of the pharmacological properties of some currently available PET-tracers is presented. Clinical studies performed with different PET ligands are also reviewed and the compound-dependent findings are summarized. An outlook is given concluding with the tailoring of tracer properties, in order to facilitate for a selective addressment of dynamic changes to the availability of a single subclass, in combination with an optimization of the quantification framework are essentials for further progress in the field of in vivo opioid receptor imaging.

Fig. 1

Radiolabelled compounds established for clinical PET-investigations of the opioid receptors.

Fig. 2

An opioid agonist binds to an opioid G-protein-coupled opioid receptor (A) activating the G protein complex by a GDP to GTP switch in the G_α subunit (B). Activated G_α and G_β/G_γ subunits move to regulate effectors (C–E) followed by phosphorylation of the C-terminal end of the receptor by G-protein receptor kinase. Arrestin binds to the phosphorylated C-terminal and binds to clathrin (F) followed by (G) phosphorylation of dynamin (D) by c-src resulting in closing of the endocytotic vesicle (H) which is formed by invagination of a clathrin-coated pit. The receptor is dephosphorylated (I) and subsequently reinserted into the membrane (J).

Fig. 3

Hypothetical sequence of events leading to changes in the receptor status and thus changes to the baseline (A) receptor binding of a tracer due to increased occupancy (B) of endogenous or exogenous opioid ligands leading potentially also to the induction of lower affinity states of the receptor (C) (decoupling/inactivation) and downregulation and reduced receptor expression (D).