Exploratory human PET study of the effectiveness of 11C-ketoprofen methyl ester, a potential biomarker of neuroinflammatory processes in Alzheimer's disease

Ohnishi, Akihito; Senda, Michio; Yamane, Toshimi; Mikami, Takuma; Nishida, Hiroyuki; Nishio, Tomoyuki; Akamatsu, Go; Ikari, Yasuhiko; Kimoto, Shogo; Aita, Kazuki; Sasaki, Masahiro; Shinkawa, Hiroko; Yamamoto, Yasuhiko; Shukuri, Miho; Mawatari, Aya; Doi, Hisashi; Watanabe, Yasuyoshi; Onoe, Hirotaka

doi:10.1016/j.nucmedbio.2016.04.005

Cited by 34 publications

(28 citation statements)

References 12 publications

(14 reference statements)

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“…Although [ 11 C ] 3 also enters human brain, 16 it does not detect neuroinflammation in Alzheimer’s disease. 17 [ 11 C]4 likely has too low an affinity for human COX-1 ( IC 50 of 47 nM) 13 to be effective for detection of COX-1 in human brain. Such a low nity would require very high concentrations of COX-1 (>250 nM) to exist in one or more brain regions to provide sufficient binding potential ( B max / K D > 5) 18 for measurement with PET using [ 11 C]4 .…”

Section: Introductionmentioning

confidence: 99%

3-Substituted 1,5-Diaryl-1H-1,2,4-triazoles as Prospective PET Radioligands for Imaging Brain COX-1 in Monkey. Part 1: Synthesis and Pharmacology

Singh

Shrestha

Cortes-Salva

et al. 2018

ACS Chem. Neurosci.

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Cyclooxygenase-1 (COX-1) is a key enzyme in the biosynthesis of proinflammatory thromboxanes and prostaglandins and is found in glial and neuronal cells within brain. COX-1 expression is implicated in numerous neuroinflammatory states. We aim to find a direct-acting positron emission tomography (PET) radioligand for imaging COX-1 in human brain as a potential biomarker of neuroinflammation and for serving as a tool in drug development. Seventeen 3-substituted 1,5-diaryl-1 H-1,2,4-triazoles were prepared as prospective COX-1 PET radioligands. From this set, three 1,5-(4-methoxyphenyl)-1 H-1,2,4-triazoles, carrying a 3-methoxy (5), 3-(1,1,1-trifluoroethoxy) (20), or 3-fluoromethoxy substituent (6), were selected for radioligand development, based mainly on their high affinities and selectivities for inhibiting human COX-1, absence of carboxyl group, moderate computed lipophilicities, and scope for radiolabeling with carbon-11 ( t = 20.4 min) or fluorine-18 ( t = 109.8 min). Methods were developed for producing [C]5, [C]20, and [ d-F]6 from hydroxy precursors in a form ready for intravenous injection for prospective evaluation in monkey with PET.

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Section: Introductionmentioning

confidence: 99%

3-Substituted 1,5-Diaryl-1H-1,2,4-triazoles as Prospective PET Radioligands for Imaging Brain COX-1 in Monkey. Part 1: Synthesis and Pharmacology

Singh

Shrestha

Cortes-Salva

et al. 2018

ACS Chem. Neurosci.

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“…Despite encouraging results in rodent models of Alzheimer’s disease (AD), 4 racemic [ 11 C]KTP-Me was unsuccessful for imaging COX-1 in the brains of human subjects that have AD or mild cognitive impairment. 5 A possible explanation is that KTP has only moderately high potency for inhibiting human COX-1 ( IC 50 = 20 nM 1 or 47 nM 6 ). Furthermore, the R -enantiomer of KTP has negligible potency for inhibiting COX-1 and its presence in the administered racemate would only have served to increase nonspecific binding relative to any COX-1 specific binding arising from the eutomer.…”

Section: Introductionmentioning

confidence: 99%

3-Substituted 1,5-Diaryl-1H-1,2,4-triazoles as Prospective PET Radioligands for Imaging Brain COX-1 in Monkey. Part 2: Selection and Evaluation of [¹¹C]PS13 for Quantitative Imaging

Shrestha

Singh

Cortes-Salva

et al. 2018

ACS Chem. Neurosci.

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In our preceding paper (Part 1), we identified three 1,5-bis-diaryl-1,2,4-triazole-based compounds that merited evaluation as potential positron emission tomography (PET) radioligands for selectively imaging cyclooxygenase-1 (COX-1) in monkey and human brain, namely, 1,5-bis(4-methoxyphenyl)-3-(alkoxy)-1 H-1,2,4-triazoles bearing a 3-methoxy (PS1), a 3-(2,2,2-trifluoroethoxy) (PS13), or a 3-fluoromethoxy substituent (PS2). PS1 and PS13 were labeled from phenol precursors by O-C-methylation with [C]iodomethane and PS2 by O-F-fluoroalkylation with [H,F]fluorobromomethane. Here, we evaluated these PET radioligands in monkey. All three radioligands gave moderately high uptake in brain, although [H,F]PS2 also showed undesirable radioactivity uptake in skull. [C]PS13 was selected for further evaluation, mainly based on more favorable brain kinetics than [C]PS1. Pharmacological preblock experiments showed that about 55% of the radioactivity uptake in brain was specifically bound to COX-1. An index of enzyme density, V, was well identified from serial brain scans and from the concentrations of parent radioligand in arterial plasma. In addition, V values were stable within 80 min, suggesting that brain uptake was not contaminated by radiometabolites. [C]PS13 successfully images and quantifies COX-1 in monkey brain, and merits further investigation for imaging COX-1 in monkey models of neuroinflammation and in healthy human subjects.

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“…However, to date, developing PET radioligands for COX-1 and COX-2 has had limited success. Shukuri et al studied 11 C-ketoprofen methyl ester, which has 62-fold higher selectivity for COX-1 than for COX-2, in rodents and humans (8)(9)(10); however, this agent is confounded by quantitation issues for the radiolabeled prodrugs, making it difficult to distinguish whether radioactivity is retained in brain because of high-affinity binding to COX-1 or merely by trapping of the negatively charged acid. With regard to PET radioligands for COX-2, no results have been published from human or nonhuman primates, although a few candidate radioligands have been studied in rodent inflammation models (11)(12)(13).…”

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confidence: 99%

Evaluation of Two Potent and Selective PET Radioligands to Image COX-1 and COX-2 in Rhesus Monkeys

et al. 2018

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This study assessed whether the newly developed PET radioligands C-PS13 andC-MC1 could image constitutive levels of cyclooxygenase (COX)-1 and COX-2, respectively, in rhesus monkeys. After intravenous injection of either radioligand, 24 whole-body PET scans were performed. To measure enzyme-specific uptake, scans of the 2 radioligands were also performed after administration of a nonradioactive drug preferential for either COX-1 or COX-2. Concurrent venous samples were obtained to measure parent radioligand concentrations. SUVs were calculated from 10 to 90 min. C-PS13 showed specific uptake in most organs, including spleen, gastrointestinal tract, kidneys, and brain, which was blocked by COX-1, but not COX-2, preferential inhibitors. Specific uptake ofC-MC1 was not observed in any organ except the ovaries and possibly kidneys. The findings suggest thatC-PS13 has adequate signal in monkeys to justify its extension to human subjects. In contrast, C-MC1 is unlikely to show significant signal in healthy humans, though it may be able to do so in inflammatory conditions.

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Exploratory human PET study of the effectiveness of 11C-ketoprofen methyl ester, a potential biomarker of neuroinflammatory processes in Alzheimer's disease

Cited by 34 publications

References 12 publications

3-Substituted 1,5-Diaryl-1H-1,2,4-triazoles as Prospective PET Radioligands for Imaging Brain COX-1 in Monkey. Part 1: Synthesis and Pharmacology

3-Substituted 1,5-Diaryl-1H-1,2,4-triazoles as Prospective PET Radioligands for Imaging Brain COX-1 in Monkey. Part 1: Synthesis and Pharmacology

3-Substituted 1,5-Diaryl-1H-1,2,4-triazoles as Prospective PET Radioligands for Imaging Brain COX-1 in Monkey. Part 2: Selection and Evaluation of [¹¹C]PS13 for Quantitative Imaging

Evaluation of Two Potent and Selective PET Radioligands to Image COX-1 and COX-2 in Rhesus Monkeys

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Exploratory human PET study of the effectiveness of 11C-ketoprofen methyl ester, a potential biomarker of neuroinflammatory processes in Alzheimer's disease

Cited by 34 publications

References 12 publications

3-Substituted 1,5-Diaryl-1H-1,2,4-triazoles as Prospective PET Radioligands for Imaging Brain COX-1 in Monkey. Part 1: Synthesis and Pharmacology

3-Substituted 1,5-Diaryl-1H-1,2,4-triazoles as Prospective PET Radioligands for Imaging Brain COX-1 in Monkey. Part 1: Synthesis and Pharmacology

3-Substituted 1,5-Diaryl-1H-1,2,4-triazoles as Prospective PET Radioligands for Imaging Brain COX-1 in Monkey. Part 2: Selection and Evaluation of [11C]PS13 for Quantitative Imaging

Evaluation of Two Potent and Selective PET Radioligands to Image COX-1 and COX-2 in Rhesus Monkeys

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3-Substituted 1,5-Diaryl-1H-1,2,4-triazoles as Prospective PET Radioligands for Imaging Brain COX-1 in Monkey. Part 2: Selection and Evaluation of [¹¹C]PS13 for Quantitative Imaging