Synthesis of [11C]MK-1064 as a new PET radioligand for imaging of orexin-2 receptor

Gao, Mingzhang; Wang, Min; Zheng, Qi

doi:10.1016/j.bmcl.2016.05.083

Cited by 19 publications

(12 citation statements)

References 33 publications

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“…Related structures were proposed by Gao et al [108] as OX2R antagonists. Roecker et al [79] developed the isoquinoline compound 53 as a candidate for labelling with a positron emitter ( Figure 5, {34}).…”

Section: Orexin Receptorsmentioning

confidence: 77%

Small-Molecule Ligands as Challenge for Positron Emission Tomography of Peptide Receptors in Neurons and Microglia of the Brain

Pissarek¹

2019

WJNS

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Neuropeptide and chemokine receptors of the G protein-coupled receptor (GPCR) family belong to different classes and subgroups providing different docking sites and special binding behavior at extracellular and also transmembrane domains for small molecules potentially suitable for positron emission tomography (PET). The contribution gives an overview updating developments of small-molecule, nonpeptide ligands at a selection of peptide and chemokine receptors, expressed in neurons and microglia of the brain, regarding the last five years. Orexin 1 and orexin 2 receptors (OX1R; OX2R) and neuropeptide Y1 and Y2 receptors (NPY1R, NPY2R) were chosen as representatives of Class A neuropeptide receptors, chemokine receptor CX3C (CX3CR1) as Class A, protein-activated receptor, highly expressed in activated microglia, and corticotropin releasing factor receptor 1 (CRFR1) as representative Class B1 receptor. Structural differences between binding domains and their endogenous ligands as well as parallel expression in different types of cells and generally low density of these receptors in brain tissue are factors making the search for selective and sensitive ligands more difficult than for classical GPCR receptors. Main progress in ligand development is observed for NPY receptor antagonists and orexin receptor antagonists. For orexin receptors, search for suitable ligands can be supported with modelling approaches, as recently the complete molecular structure of these receptors is available. Small molecules, binding at CRFR1, as for other Class B1 receptor ligands, in PET and investigations of pharmacodynamics revealed rather allosteric binding modes, although, the complete crystal structure of CRFR1 as prototype of Class B1 provides, hitherto, improved possibilities for understanding binding mechanisms. Highly specific as a marker of microglia among How to cite this paper: Pissarek, M. (2019) Small-Molecule Ligands as Challenge for Positron Emission Tomography of Peptide Receptors in Neurons and Microglia of the Brain. World Journal of Neuroscience, 9, 294-327.

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Section: Orexin Receptorsmentioning

confidence: 77%

Small-Molecule Ligands as Challenge for Positron Emission Tomography of Peptide Receptors in Neurons and Microglia of the Brain

Pissarek¹

2019

WJNS

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“…At the end of synthesis (EOS), the SA of [ 11 C]-tracer was determined again by analytical HPLC (Zheng and Mock, 2005), calculated, decay corrected to EOB, and based on [ 11 C]CO 2 , which was in agreement with the 'on line' determined value. In each our [ 11 C]-tracer production, if semi-preparative HPLC was used for purification, then the SA of [ 11 C]-tracer was assessed by both semi-preparative HPLC (during synthesis) and analytical HPLC (EOS); if SPE was used for purification, then the SA of [ 11 C]-tracer was only measured by analytical HPLC at EOS (Gao et al, 2016b).…”

Section: Insert Scheme 2 About Herementioning

confidence: 99%

Synthesis of N -(3-(4-[ 11 C]methylpiperazin-1-yl)−1-(5-methylpyridin-2-yl)−1 H -pyrazol-5-yl)pyrazolo[1,5- a ]pyrimidine-3-carboxamide as a new potential PET agent for imaging of IRAK4 enzyme in neuroinflammation

Wang

Miao

et al. 2018

Applied Radiation and Isotopes

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The reference standard N-(3-(4-methylpiperazin-1-yl)-1-(5-methylpyridin-2-yl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (9) and its demethylated precursor N-(1-(5-methylpyridin-2-yl)-3-(piperazin-1-yl)-1H-pyrazol-5-yl)pyrazolo[1,5-α]pyrimidine-3-carboxamide (8) were synthesized from pyrazolo[1,5-a]pyrimidine-3-carboxylic acid and ethyl 2-cyanoacetate with overall chemical yield 13% in nine steps and 14% in eight steps, respectively. The target tracer N-(3-(4-[C]methylpiperazin-1-yl)-1-(5-methylpyridin-2-yl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide ([C]9) was prepared from its precursor with [C]CHOTf through N-[C]methylation and isolated by HPLC combined with SPE in 50-60% radiochemical yield, based on [C]CO and decay corrected to EOB. The radiochemical purity was >99%, and the specific activity at EOB was 370-1110 GBq/μmol.

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“…To bridge the gap, several orexin antagonists have been radiolabeled by our group, as well as others. Most of the early discovery attempts resulted in compounds with low brain uptake or strong P-glycoprotein (P-gp) binding, including [ 11 C]MK-1064 [26], [ 11 C]EMPA [27], [ 11 C]BBAC [28], and [ 11 C]CW4 [29] (Figure 1). Towards the development of a successful OXR brain-PET imaging probe, we report the discovery and evaluation of [ 11 C]CW24 with good brain uptake, suitable metabolic stability, and pharmacokinetics based on animal imaging studies in rodents and non-human primates.…”

Section: Introductionmentioning

confidence: 99%

A New Positron Emission Tomography Probe for Orexin Receptors Neuroimaging

Bai

Placzek

et al. 2020

Molecules

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The orexin receptor (OX) is critically involved in motivation and sleep−wake regulation and holds promising therapeutic potential in various mood disorders. To further investigate the role of orexin receptors (OXRs) in the living human brain and to evaluate the treatment potential of orexin-targeting therapeutics, we herein report a novel PET probe ([11C]CW24) for OXRs in the brain. CW24 has moderate binding affinity for OXRs (IC50 = 0.253 μM and 1.406 μM for OX1R and OX2R, respectively) and shows good selectivity to OXRs over 40 other central nervous system (CNS) targets. [11C]CW24 has high brain uptake in rodents and nonhuman primates, suitable metabolic stability, and appropriate distribution and pharmacokinetics for brain positron emission tomography (PET) imaging. [11C]CW24 warrants further evaluation as a PET imaging probe of OXRs in the brain.

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Synthesis of [11C]MK-1064 as a new PET radioligand for imaging of orexin-2 receptor

Abstract: Abstract-The reference standard MK

Cited by 19 publications

References 33 publications

Small-Molecule Ligands as Challenge for Positron Emission Tomography of Peptide Receptors in Neurons and Microglia of the Brain

Small-Molecule Ligands as Challenge for Positron Emission Tomography of Peptide Receptors in Neurons and Microglia of the Brain

Synthesis of N -(3-(4-[ 11 C]methylpiperazin-1-yl)−1-(5-methylpyridin-2-yl)−1 H -pyrazol-5-yl)pyrazolo[1,5- a ]pyrimidine-3-carboxamide as a new potential PET agent for imaging of IRAK4 enzyme in neuroinflammation

A New Positron Emission Tomography Probe for Orexin Receptors Neuroimaging

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