A Survey of Molecular Imaging of Opioid Receptors

Abstract

The discovery of endogenous peptide ligands for morphine binding sites occurred in parallel with the identification of three subclasses of opioid receptor (OR), traditionally designated as μ, δ, and κ, along with the more recently defined opioid-receptor-like (ORL1) receptor. Early efforts in opioid receptor radiochemistry focused on the structure of the prototype agonist ligand, morphine, although N-[methyl-11C]morphine, -codeine and -heroin did not show significant binding in vivo. [11C]Diprenorphine ([11C]DPN), an orvinol type, non-selective OR antagonist ligand, was among the first successful PET tracers for molecular brain imaging, but has been largely supplanted in research studies by the μ-preferring agonist [11C]carfentanil ([11C]Caf). These two tracers have the property of being displaceable by endogenous opioid peptides in living brain, thus potentially serving in a competition-binding model. Indeed, many clinical PET studies with [11C]DPN or [11C]Caf affirm the release of endogenous opioids in response to painful stimuli. Numerous other PET studies implicate μ-OR signaling in aspects of human personality and vulnerability to drug dependence, but there have been very few clinical PET studies of μORs in neurological disorders. Tracers based on naltrindole, a non-peptide antagonist of the δ-preferring endogenous opioid enkephalin, have been used in PET studies of δORs, and [11C]GR103545 is validated for studies of κORs. Structures such as [11C]NOP-1A show selective binding at ORL-1 receptors in living brain. However, there is scant documentation of δ-, κ-, or ORL1 receptors in healthy human brain or in neurological and psychiatric disorders; here, clinical PET research must catch up with recent progress in radiopharmaceutical chemistry.

Naloxone precipitated withdrawal increases dopamine release in the dorsal striatum of opioid dependent men

“…We observed significant increases in plasma cortisol and in pituitary R1 (see the “Methods” section) that were consistent with HPA hyperactivity during NPW [ 78 ]. Opioid and DA receptors modulate HPA function [ 79 ], for example, MOR is highly expressed in the pituitary [ 40 ]. The positive association between increases in pituitary R1 and striatal DA release could reflect concomitant effects of NAL on the pituitary and DA systems [ 80 , 81 ].…”

“…We also performed exploratory analyses to assess the effect of NPW on R1 in the pituitary and habenula ROIs. The pituitary has high MOR levels [ 39 , 40 ], is a major source of endorphins (endogenous MOR agonist), and modulates the HPA response during NPW. Increases in pituitary R1 (measured with PET) have been observed in conditions that trigger the release of pituitary hormones [ 41 ].…”

Seasonal Variation in the Brain μ-Opioid Receptor Availability

“…Technically, while [ 11 C]carfentanil BP ND in baseline condition is proportional to MOR density, the exact contributions of MOR density, receptor affinity, and baseline occupancy by endogenous opioids cannot be assessed in a single measurement ( Mintun et al, 1984 ; Henriksen and Willoch, 2008 ), and these components cannot be differentiated in a single scan. [ 11 C]carfentanil is an agonist tracer preferably binding MORs in the high-affinity state ( Henriksen and Willoch, 2008 ; Cumming et al, 2019 ) and has low test–retest variability in PET imaging ( Hirvonen et al, 2009 ). Although endogenous opioids compete for binding sites with [ 11 C]carfentanil ( Quelch et al, 2014 ; Saanijoki et al, 2018 ), the basal opioid concentrations are often very low, at least in rats ( Maidment et al, 1989 ).…”

NMR Analysis of a Series of 6,14‐Ethenomorphinan Derivatives as PET Precursors and Reference Substances**

“…[8] Recently, Lever et al reported the synthesis and opioid receptor binding properties of 111 In-labelled diprenorphine DOTA conjugates for imaging by means of single photon emission computer tomography (SPECT). [9] In the last two decades, comprehensive reviews [8,[10][11][12] have summarized the diversity of radiotracers available in the field of opioid receptor imaging.…”