Positron emission tomography radioligands for the opioid system

Dannals, Robert F.

doi:10.1002/jlcr.3005

Cited by 18 publications

(27 citation statements)

References 72 publications

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“…They include 11 C-carfentanil, 11 C-/ 18 F-diprenorphine, 11 C-buprenorphine, 11 C-cyclofoxy, and 11 C-methylnaltrindole (for reviews, see (19, 20)). None of these ligands can be used to selectively image KOR in vivo.…”

Section: Introductionmentioning

confidence: 99%

An Improved Antagonist Radiotracer for the κ-Opioid Receptor: Synthesis and Characterization of ¹¹C-LY2459989

et al. 2014

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The kappa opioid receptors (KOR) are implicated in a number of neuropsychiatric diseases and addictive disorders. Positron Emission Tomography (PET) with radioligands provides a means to image the KOR in vivo and investigate its function in health and disease. The purpose of this study was to develop the selective KOR antagonist 11C-LY2459989 as a PET radioligand and characterize its imaging performance in non-human primates. Methods LY2459989 was synthesized and assayed for in vitro binding to opioid receptors. Ex vivo studies in rodents were conducted to assess its potential as a tracer candidate. 11C-LY2459989 was synthesized by reaction of its iodophenyl precursor with 11C-cyanide followed by partial hydrolysis of the resulting 11C-cyanophenyl intermediate. Imaging experiments with 11C-LY2459989 were carried out in rhesus monkeys with arterial input function measurement. Imaging data were analyzed with kinetic models to derive in vivo binding parameters. Results LY2459989 is a full antagonist with high binding affinity and selectivity for KOR (Ki = 0.18, 7.68, and 91.3 nM, respectively, for κ, μ, and δ receptors). Ex vivo studies in rats indicated LY2459989 as an appropriate tracer candidate with high specific binding signals, and confirmed its KOR binding selectivity in vivo. 11C-LY2459989 was synthesized in high radiochemical purity and good specific activity. In rhesus monkeys, 11C-LY2459989 displayed a fast rate of peripheral metabolism. Similarly, 11C-LY2459989 displayed fast uptake kinetics in the brain and an uptake pattern consistent with the distribution of KOR in primates. Pretreatment with naloxone (1 mg/kg, i.v.) resulted in a uniform distribution of radioactivity in the brain. Further, specific binding of 11C-LY2459989 was dose-dependently reduced by the selective KOR antagonist LY2456302 and the unlabeled LY2459989. Regional binding potential (BPND) values derived from the multilinear analysis method (MA1), as a measure of in vivo specific binding signal, were 2.18, 1.39, 1.08, 1.04, 1.03, 0.59, 0.51, 0.50, respectively, for the globus pallidus, cingulate cortex, insula, caudate, putamen, frontal cortex, temporal cortex, and thalamus. Conclusion The novel PET radioligand 11C-LY2459989 displayed favorable pharmacokinetic properties, specific and KOR-selective binding profile, and high specific binding signals in vivo, thus making it a promising PET imaging agent for KOR.

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Section: Introductionmentioning

confidence: 99%

An Improved Antagonist Radiotracer for the κ-Opioid Receptor: Synthesis and Characterization of ¹¹C-LY2459989

et al. 2014

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“…The highest fractions of expression of any subtype are found in the substantia nigra (66% KOR) and the thalamus (67% MOR), reflecting the need for a subtype-selective radioligand with sufficient binding selectivity in vivo when attempting to study the function and role of a single OR in the brain. 1 − 7 In recent years, a new interest in OR radioligands developed, for example, because of an opioid abuse crisis. The limited availability, toxicity, and short half-life of [ 11 C]carfentanil, which is the only MOR-selective positron emission tomography (PET) ligand in use, prompted us to explore an alternative path.…”

Section: Introductionmentioning

confidence: 99%

Pharmacological Characterization of Low-to-Moderate Affinity Opioid Receptor Agonists and Brain Imaging with ¹⁸F-Labeled Derivatives in Rats

et al. 2020

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The 3,4-dichloro- N -(1-(dimethylamino)cyclohexyl)methyl benzamide scaffold was studied as a template for 18 F-positron emission tomography ( 18 F-PET) radiotracer development emphasizing sensitivity to changes in opioid receptor (OR) occupancy over high affinity. Agonist potency, binding affinity, and relevant pharmacological parameters of 15 candidates were investigated. Two promising compounds 3b and 3e with μ-OR (MOR) selective agonist activity in the moderate range (EC 50 = 1–100 nM) were subjected to 18 F-fluorination, autoradiography, and small-animal PET imaging. Radioligands [ 18 F] 3b and [ 18 F] 3e were obtained in activity yields of 21 ± 5 and 23 ± 4% and molar activities of 25–40 and 200–300 GBq/μmol, respectively. Displaceable binding matching MOR distribution in the brain was confirmed by imaging. Radioligands showed a rapid pharmacokinetic profile; however, metabolite-corrected, blood-based modeling was required for data analysis. Observed BP ND was low, although treatment with naloxone leads to a marked decrease in specific binding, confirming the discovery of a new template for 18 F-labeled OR-agonist PET ligands.

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“…Most opioid receptor radioligands, such as [ 11 C]carfentanil and [ 11 C]N1´-methylnaltrindole, were designed for brain imaging [19,20]. They are necessarily lipophilic to foster bloodbrain barrier penetration.…”

Section: Introductionmentioning

confidence: 99%

Design, synthesis and evaluation of 111In labeled DOTA-conjugated tetrapeptides having high affinity and selectivity for mu opioid receptors

Lever

Fergason-Cantrell

Carmack

et al. 2019

Nuclear Medicine and Biology

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Introduction-Peripheral mu (μ) opioid receptors are implicated in pain, bowel dysfunction and the progression of certain cancers. In an effort to identify radioligands well suited for imaging these peripheral sites, we have prepared and evaluated four hydrophilic [ 111 In]-labeled, DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) conjugated μ tetrapeptides. Methods-Peptides were prepared by solid-phase techniques, using orthogonal strategies to achieve branching to DOTA, and then characterized by HPLC, mass spectroscopy and amino acid analysis. Scaffolds included novel peptide H-Dmt-D-Ala-Phe-Orn-NH 2 (DAPO), where Dmt = 2´, 6´-dimethyltyrosine, and known peptide H-Dmt-D-Arg-Phe-Lys-NH 2 ([Dmt 1 ]DALDA). Constructs had DOTA conjugation at the Orn 4 or Lys 4 side chains, or to the C-terminal through a hexanoic acid-lysine linker. Indium(III) complexation and [ 111 In]-radiolabeling were accomplished by standard methods. Protein binding and Log D 7.4 were determined. Binding and pharmacological profiles were obtained in vitro. Biodistribution and radiometabolite studies were conducted using male CD-1 mice. Results-All four indium(III)-DOTA conjugates derived from DAPO and [Dmt 1 ]DALDA showed good selectivity and subnanomolar affinity for μ opioid receptors. One radioligand, H-Dmt-D-Ala-Phe-Orn(δ-[ 111 In]DOTA)-NH 2 , showed 25% specific binding in vivo to μ sites in mouse gut. Notably, this was the least polar of the series, and also showed low sensitivity to modulation of binding by sodium ions. All radioligands showed high kidney uptake of radiometabolites.

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Positron emission tomography radioligands for the opioid system

Cited by 18 publications

References 72 publications

An Improved Antagonist Radiotracer for the κ-Opioid Receptor: Synthesis and Characterization of ¹¹C-LY2459989

An Improved Antagonist Radiotracer for the κ-Opioid Receptor: Synthesis and Characterization of ¹¹C-LY2459989

Pharmacological Characterization of Low-to-Moderate Affinity Opioid Receptor Agonists and Brain Imaging with ¹⁸F-Labeled Derivatives in Rats

Design, synthesis and evaluation of 111In labeled DOTA-conjugated tetrapeptides having high affinity and selectivity for mu opioid receptors

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Positron emission tomography radioligands for the opioid system

Cited by 18 publications

References 72 publications

An Improved Antagonist Radiotracer for the κ-Opioid Receptor: Synthesis and Characterization of 11C-LY2459989

An Improved Antagonist Radiotracer for the κ-Opioid Receptor: Synthesis and Characterization of 11C-LY2459989

Pharmacological Characterization of Low-to-Moderate Affinity Opioid Receptor Agonists and Brain Imaging with 18F-Labeled Derivatives in Rats

Design, synthesis and evaluation of 111In labeled DOTA-conjugated tetrapeptides having high affinity and selectivity for mu opioid receptors

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An Improved Antagonist Radiotracer for the κ-Opioid Receptor: Synthesis and Characterization of ¹¹C-LY2459989

An Improved Antagonist Radiotracer for the κ-Opioid Receptor: Synthesis and Characterization of ¹¹C-LY2459989

Pharmacological Characterization of Low-to-Moderate Affinity Opioid Receptor Agonists and Brain Imaging with ¹⁸F-Labeled Derivatives in Rats