Evaluation of the kappa-opioid receptor-selective tracer [11C]GR103545 in awake rhesus macaques

Schoultz, Bent W.; Hjørnevik, Trine; Willoch, Frode; Marton, János; Noda, Akihiro; Murakami, Yoshihiro; Miyoshi, Sosuke; Nishimura, Shintaro; Årstad, Erik; Drzezga, Alexander; Matsunari, Ichiro; Henriksen, Gjermund

doi:10.1007/s00259-010-1384-6

Cited by 30 publications

(39 citation statements)

References 19 publications

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“…The slope of this regression line represented the estimate of in vivo K D for [ 11 C]GR103545. The in vivo K D values are in excellent agreement with the inhibition coefficient ( K i ) of 0.02 nmol/L measured in vitro (Schoultz et al., 2010) using cloned human KOR, and the in vivo K D estimate of 0.048 nmol/L derived from [ 11 C]GR103545 PET imaging study in rhesus monkey (Tomasi et al, 2013). The relationship between BP F and in vitro B max was also evaluated using B max values from individual studies.…”

Section: Resultssupporting

confidence: 75%

“…[ 11 C]GR103545 has been studied previously in awake monkey (Schoultz et al, 2010) and anesthetized baboon (Talbot et al, 2005). Compared to these studies, metabolism of [ 11 C]GR103545 was slower in human, with parent fractions of 67% and 47% at 30 and 60 min post injection, vs. 49% and 35% in rhesus monkey, and 35% and 25% in baboon, respectively (Schoultz et al, 2010; Talbot et al, 2005). Plasma free fraction was similar among human, monkey, and baboon (20% in human, 22% in monkey, and 24% in baboon).…”

Section: Discussionmentioning

confidence: 99%

“…In non-human primate studies, the 2TC model was chosen as the method of choice for the analysis of TACs and derivation of kinetic parameters (Schoultz et al, 2010; Talbot et al, 2005). Similarly, the 2TC model provided a better fit in all regions than the 1TC model in humans.…”

Section: Discussionmentioning

confidence: 99%

“…In in vitro radioligand competition assays using recombinant cells expressing KOR, MOR or DOR, GR103545 was shown to bind to KOR with high affinity ( K i of 0.02 ± 0.01 nmol/L) and excellent selectivity over MOR ( K i of 16 ± 5 nmol/L) and DOR ( K i of 536 ± 234 nmol/L) (Schoultz et al, 2010). In initial in vivo evaluations in non-human primates (Schoultz et al, 2010; Talbot et al, 2005) [ 11 C]GR103545 was shown to have favorable characteristics: excellent brain penetration, significant washout, moderate metabolic rate in the plasma, and good specific binding signals. The uptake pattern of [ 11 C]GR103545 was in good agreement with the known distribution of KOR in the non-human primate brain.…”

Section: Introductionmentioning

confidence: 99%

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Evaluation of the agonist PET radioligand [11C]GR103545 to image kappa opioid receptor in humans: Kinetic model selection, test–retest reproducibility and receptor occupancy by the antagonist PF-04455242

et al. 2014

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Introduction Kappa opioid receptors (KOR) are implicated in several brain disorders. In this report, a first-in-human Positron Emission Tomography (PET) study was conducted with the potent and selective KOR agonist tracer, [11C]GR103545, to determine an appropriate kinetic model for analysis of PET imaging data and assess the test-retest reproducibility of model-derived binding parameters. The non-displaceable distribution volume (VND) was estimated from a blocking study with naltrexone. In addition, KOR occupancy of PF-04455242, a selective KOR antagonist that is active in preclinical models of depression, was also investigated. Methods For determination of a kinetic model and evaluation of test-retest reproducibility, 11 subjects were scanned twice with [11C]GR103545. Seven subjects were scanned before and 75 min after oral administration of naltrexone (150 mg). For the KOR occupancy study, six subjects were scanned at baseline and 1.5 h and 8 h after an oral dose of PF-04455242 (15 mg, n = 1 and 30 mg, n = 5). Metabolite-corrected arterial input functions were measured and all scans were 150 min in duration. Regional time-activity curves (TACs) were analyzed with 1- and 2-tissue compartment models (1TC and 2TC) and the multilinear analysis (MA1) method to derive regional volume of distribution (VT). Relative test-retest variability (TRV), absolute test-retest variability (aTRV) and intra-class coefficient (ICC) were calculated to assess test-retest reproducibility of regional VT. Occupancy plots were computed for blocking studies to estimate occupancy and VND. The half maximal inhibitory concentration (IC50) of PF-04455242 was determined from occupancies and drug concentrations in plasma. [11C]GR103545 in vivo KD was also estimated. Results Regional TACs were well described by the 2TC model and MA1. However, 2TC VT was sometimes estimated with high standard error. Thus MA1 was the model of choice. Test-retest variability was ~15%, depending on the outcome measure. The blocking studies with naltrexone and PF-04455242 showed that VT was reduced in all regions; thus no suitable reference region is available for the radiotracer. VND was estimated reliably from the occupancy plot of naltrexone blocking (VND = 3.4 ± 0.9 mL/cm3). The IC50 of PF-04455242 was calculated as 55 ng/mL. [11C]GR103545 in vivo KD value was estimated as 0.069 nmol/L. Conclusions [11C]GR103545 PET can be used to image and quantify KOR in humans, although it has slow kinetics and variability of model-derived kinetic parameters is higher than desirable. This tracer should be suitable for use in receptor occupancy studies, particularly those that target high occupancy.

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Section: Resultssupporting

confidence: 75%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Evaluation of the agonist PET radioligand [11C]GR103545 to image kappa opioid receptor in humans: Kinetic model selection, test–retest reproducibility and receptor occupancy by the antagonist PF-04455242

et al. 2014

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“…Thus, DYNs released in response to strong stimuli may decrease function of mossy fiber pathway synapses that have low levels of activity, suggesting DYN/KOR modulation of synaptic transmission appears to be synapse-selective and highly dependent on activity. DYN released from dendrites and/or local collaterals of dentate gyrus granule cells may act in a retrograde fashion and activate KORs on perforant path terminals arising from the entorhinal cortex resulting in inhibition of entorhinal cortex inputs to the dentate gyrus [224,226]. Retrograde signaling by DYN has been reported in the hypothalamus [39], suggesting that retrograde signaling may extend to other DYN-rich regions.…”

Section: Hippocampusmentioning

confidence: 99%

The dynorphin/κ-opioid receptor system and its role in psychiatric disorders

Tejeda

Shippenberg

Henriksson

2011

Cell. Mol. Life Sci.

148

144

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The dynorphin/κ-opioid receptor system has been implicated in the pathogenesis and pathophysiology of several psychiatric disorders. In the present review, we present evidence indicating a key role for this system in modulating neurotransmission in brain circuits that subserve mood, motivation, and cognitive function. We overview the pharmacology, signaling, post-translational, post-transcriptional, transcriptional, epigenetic and cis regulation of the dynorphin/κ-opioid receptor system, and critically review functional neuroanatomical, neurochemical, and pharmacological evidence, suggesting that alterations in this system may contribute to affective disorders, drug addiction, and schizophrenia. We also overview the dynorphin/κ-opioid receptor system in the genetics of psychiatric disorders and discuss implications of the reviewed material for therapeutics development.

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Synthesis and Pharmacological Evaluation of Fluorinated Quinoxaline‐Based κ‐Opioid Receptor (KOR) Agonists Designed for PET Studies

et al. 2020

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k-Opioid receptors (KORs) play a predominant role in pain alleviation, itching skin diseases, depression and neurodegenerative disorders such as multiple sclerosis. Therefore, imaging of KOR by a fluorinated PET tracer was envisaged. Two strategies were followed to introduce a F atom into the very potent class of cis,transconfigured perhydroquinoxalines. Whereas the synthesis of fluoroethyltriazole 2 has already been reported, fluoropyrrolidines 14 (1-[2-(3,4-dichlorophenyl)acetyl]-8-[(R)-3-fluoropyrrolidin-1-yl]-perhydroquinoxalines) were prepared by S N 2 substitution of a cyclic sulfuric acid derivative with hydroxypyrrolidine and subsequent transformation of the OH moiety into a F substituent. Fluoropyrrolidines 14 showed similar low-nanomolar KOR affinity and selectivity to the corresponding pyrrolidines, but the corresponding alcohols were slightly less active. In the cAMP and β-arrestin assay, 14b (proton at the 4-position) exhibited similar KOR agonistic activity as U-50,488. The fluoro derivatives 14b and 14c (CO 2 CH 3 at the 4-position) revealed KOR-mediated anti-inflammatory activity as CD11c and the IFN-γ production were reduced significantly in mouse and human dendritic cells. Compounds 14b and 14-c also displayed antiinflammatory and immunomodulatory activity in mouse and human T cells. The PET tracer [ 18 F]-2 was prepared by 1,3-dipolar cycloaddition. In vivo, [ 18 F]-2 did not label KOR due to very fast elimination kinetics. Nucleophilic substitution of a mesylate precursor provided [ 18 F]-14c. Unfortunately, defluorination of [ 18 F]-14c occurred in vivo, which was analyzed in detail by in vitro studies.

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Evaluation of the kappa-opioid receptor-selective tracer [11C]GR103545 in awake rhesus macaques

Abstract: [(11)C]GR103545 is selective for kappa-OR and holds promise for use to selectively depict and quantify this receptor in humans by means of PET.

Cited by 30 publications

References 19 publications

Evaluation of the agonist PET radioligand [11C]GR103545 to image kappa opioid receptor in humans: Kinetic model selection, test–retest reproducibility and receptor occupancy by the antagonist PF-04455242

Evaluation of the agonist PET radioligand [11C]GR103545 to image kappa opioid receptor in humans: Kinetic model selection, test–retest reproducibility and receptor occupancy by the antagonist PF-04455242

The dynorphin/κ-opioid receptor system and its role in psychiatric disorders

Synthesis and Pharmacological Evaluation of Fluorinated Quinoxaline‐Based κ‐Opioid Receptor (KOR) Agonists Designed for PET Studies

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