Recent development and potential use of µ‐ and κ‐opioid receptor ligands in positron emission tomography studies

Henriksen, Gjermund; Willoch, Frode; Talbot, Peter S.; Wester, Hans

doi:10.1002/ddr.20161

Cited by 10 publications

(10 citation statements)

References 152 publications

(135 reference statements)

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“…Stimulation of the μ-OR is mainly responsible for the reinforcing effects of opioid drugs, although δ-ORs may also contribute (Self and Stein, 1992 ). The κ-OR is also involved in the responses to addictive drugs, particularly cocaine, but also to opiates (for recent reviews see Prisinzano et al ., 2005; Henriksen et al ., 2006 ). Different drugs of abuse stimulate dopamine release in the ventral striatum, which includes the nucleus accumbens.…”

Section: Opioid Receptor Studies In Humansmentioning

confidence: 99%

Imaging of opioid receptors in the central nervous system

Henriksen

Willoch

2007

Brain

Self Cite

182

132

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In vivo functional imaging by means of positron emission tomography (PET) is the sole method for providing a quantitative measurement of μ-, κ and δ-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.

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Section: Opioid Receptor Studies In Humansmentioning

confidence: 99%

Imaging of opioid receptors in the central nervous system

Henriksen

Willoch

2007

Brain

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182

132

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“…First, we measured the ED 50 of LY2795050 at MOR using an occupancy model and [ 11 C]carfentanil, a selective MOR tracer (19). Second, we measured the ED 50 of LY2795050 at KOR using one- and two-site binding models and [ 11 C]LY2795050 as radiotracer.…”

Section: Introductionmentioning

confidence: 99%

Determination of the In Vivo Selectivity of a New κ-Opioid Receptor Antagonist PET Tracer ¹¹C-LY2795050 in the Rhesus Monkey

et al. 2013

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[11C]LY2795050 is a novel kappa-selective antagonist PET tracer. The in vitro binding affinities (Ki) of LY2795050 at the kappa opioid (KOR) and mu opioid (MOR) receptors are 0.72 and 25.8 nM, respectively. Thus, the in vitro KOR/MOR binding selectivity is about 36:1. Our goal in this study was to determine the in vivo selectivity of this new KOR antagonist tracer in the monkey. Methods To estimate ED50 value of LY2795050 at the MOR and KOR sites, two series of blocking experiments were performed in three rhesus monkeys using [11C]LY2795050 and [11C]carfentanil with co-injections of various doses of unlabeled LY2795050. Kinetic modeling was applied to calculate regional binding potential (BPND), and one- and two-site binding curves were fitted to these data to measure [11C]LY2795050 binding selectivity. Results LY2795050 ED50 at MOR was 119 μg/kg based on a one-site model for [11C]carfentanil. The one-site binding model was also deemed sufficient to describe the specific binding of [11C]LY2795050 at KOR. The ED50 at KOR estimated from the one-site model was 15.6 μg/kg. Thus the ED50 ratio for MOR:KOR was 7.6. Conclusion The in vivo selectivity of [11C]LY2795050 for KOR over MOR is 7.6. [11C]LY2795050 has 4.7-fold lower selectivity at KOR over MOR in vivo as compared to in vitro. Nevertheless, based on our finding in vivo, 88 % of the PET-observed specific binding of [11C]LY2795050 under baseline condition will be due to binding of the tracer at the KOR site in a region with similar prevalence of KOR and MOR. We conclude that [11C]LY2795050 is sufficiently selective for KOR over MOR in vivo to be considered an appropriate probe for studying the kappa opioid receptor with PET.

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“…Modifications to the original synthesis have been plentiful including the substitution of [ 11 C]methyl triflate for [ 11 C]iodomethane and use of a loop methylation system and perhaps the most unique and extraordinarily simple purification of the neuroreceptor radiotracer using an anion extraction disk to remove the carboxylic acid precursor starting material in a single step …”

Section: μ‐Selective Radiotracersmentioning

confidence: 99%

“…3,22 Modifications to the original synthesis have been plentiful including the substitution of [ 11 C]methyl triflate for [ 11 C]iodomethane and use of a loop methylation system 23 and perhaps the most unique and extraordinarily simple purification of the neuroreceptor radiotracer using an anion extraction disk to remove the carboxylic acid precursor starting material in a single step. 24 Drawing upon the successful use of [ 11 C]carfentanil as a m-selective opiate PET receptor radioligand, some investigators pursued the development of fentanyl/carfentanil analogs incorporating longer-lived fluorine-18 while others seeking improved in vivo properties synthesized structurally similar analogs. In 1986, researchers at Brookhaven National Laboratory prepared a fluorinated derivative of fentanyl ( Figure 3) at moderate specific activity from [ 18 F]fluoride ion.…”

Section: M-selective Radiotracersmentioning

confidence: 99%

Positron emission tomography radioligands for the opioid system

Dannals

2013

Labelled Comp Radiopharmac

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Opiate receptors are found in the brain, the spinal cord, some peripheral sensory neurons, and the gastrointestinal tract. Naturally occurring and synthetic opiate ligands exert their influence on a wide variety of processes including analgesia, euphoria, dysphoria, sedation, respiratory depression, and miosis and are frequently topics for discussions on addiction and physical dependence. This review looks at the history of positron emission tomography radioligands for probing this receptor system.

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Recent development and potential use of µ‐ and κ‐opioid receptor ligands in positron emission tomography studies

Cited by 10 publications

References 152 publications

Imaging of opioid receptors in the central nervous system

Imaging of opioid receptors in the central nervous system

Determination of the In Vivo Selectivity of a New κ-Opioid Receptor Antagonist PET Tracer ¹¹C-LY2795050 in the Rhesus Monkey

Positron emission tomography radioligands for the opioid system

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Recent development and potential use of µ‐ and κ‐opioid receptor ligands in positron emission tomography studies

Cited by 10 publications

References 152 publications

Imaging of opioid receptors in the central nervous system

Imaging of opioid receptors in the central nervous system

Determination of the In Vivo Selectivity of a New κ-Opioid Receptor Antagonist PET Tracer 11C-LY2795050 in the Rhesus Monkey

Positron emission tomography radioligands for the opioid system

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Determination of the In Vivo Selectivity of a New κ-Opioid Receptor Antagonist PET Tracer ¹¹C-LY2795050 in the Rhesus Monkey