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| Names | |
|---|---|
| IUPAC name methyl (3R)-4-[2-(3,4-dichlorophenyl)acetyl]-3-(pyrrolidin-1-ylmethyl)piperazine-1-carboxylate | |
| Other names GR-103545; 860VEX6583; GR103545 | |
| Identifiers | |
3D model (JSmol) | |
| ChEMBL | |
| ChemSpider | |
| UNII | |
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| Properties | |
| C19H25Cl2N3O3 | |
| Molar mass | 414.3 g/mol |
Except where otherwise noted, data are given for materials in theirstandard state (at 25 °C [77 °F], 100 kPa). | |
GR-103545 is apotent andhighly selectiveκ-opioid receptor (KOR)agonist primarily employed as aradioligand inpositron emission tomography (PET)neuroimaging research.[1][2][3] Whenradiolabeled with carbon-11, [11C]GR-103545 serves as a neuroimaging tracer for quantifying KOR availability andreceptor occupancy in the human brain.[1]
GR-103545 acts as anagonist of theκ-opioid receptor (KOR), exhibitinghigh selectivity over otheropioid receptor subtypes.[1] The compound represents the active (−)-enantiomer of theracemic mixtureGR-89696.[3]
Based onIn vitroradioligand competitionassays using recombinant cells expressing humanopioid receptors GR-103545 binds to KOR with highaffinity (Ki = 0.02 ± 0.01 nmol/L) and exhibits substantialselectivity overμ-opioid receptors (Ki = 16 ± 5 nmol/L) andδ-opioid receptors (Ki = 536 ± 234 nmol/L).[1] It is approximately 800-fold selective for KOR over μ-opioid and even more selective over δ-opioid receptors.[1] Thein vivodissociation constant (KD) of [11C]GR-103545 has been estimated at 0.069 nmol/L in humans and 0.048 nmol/L inrhesus macaques.[1][2][4]
The highestbinding potential values based on [11C] radioligand are observed in theamygdala,anterior cingulate cortex, andinsula.[1][3] Intermediate binding is detected in thetemporal lobe,frontal lobe,globus pallidus, andputamen, while lower binding is observed in theoccipital lobe,caudate nucleus,hippocampus,posterior cingulate cortex,cerebellum, andthalamus.[1][2][3] Intiti monkeys the highest binding was observed in thepituitary gland, followed by the insula,claustrum, andorbitofrontal cortex.[2]
[11C]GR-103545 demonstrates favorable properties forPET imaging, including highbrain penetration, and good specific binding signals innon-human primates and humans, although it has slow kinetics and variability of kinetic parameters is higher than desirable.[1][3][4] Followingintravenous administration, theradiotracer exhibits relatively slow kinetics in human brain tissue, with uptake reachingplateau at approximately 100 minutes post-injection in high-binding regions.[1] The non-displaceabledistribution volume (VND) has been estimated at 3.4 ± 0.9 mL/cm3 usingnaltrexone blocking studies.[1]Test-retest reproducibility studies have shown relative variability of approximately 15% for regionalvolume of distribution measurements.[1]
Imaging with [11C]GR-103545 has been employed to investigateκ-opioid receptor (KOR) involvement incocaine use disorder.[5] One study have demonstrated an association between KOR availability andcocaineself-administration behavior, with greater KOR binding associated with increased cocaine-seeking.[5] Additionally, cocainebinge administration has been shown to reduce theradioligand's binding by 18% in thestriatum and 14% across other brain regions.[5]