Synthesis and biological evaluation of novel 18F-labeled phenylbenzofuran-2-carboxamide derivative for detection of orexin 1 receptor in the brain

Watanabe, Hiroyuki; Idoko, Yuki; Iikuni, Shimpei; Ide, Takuji; Shimizu, Yoichi; Nakamoto, Yuji; Ono, Masahiro

doi:10.1016/j.bmcl.2021.128098

Cited by 6 publications

(12 citation statements)

References 22 publications

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“…Non-subtype-selective OXR ligand suvorexant compared to the OX1R-selective ligand JH112 (22). B: Examples of subtype-selective PET ligand candidates investigated so far (14,15,(19)(20)(21). C: Fluorine-substituted derivatives 1a-f studied in this work.…”

Section: Figure 1 Overview Of Oxr Ligands Amentioning

confidence: 99%

“…Most of these efforts addressed OX2R-selective PET ligand candidates (Figure 1B; [ 11 C]CW4 (14), [ 18 F]seltorexant (15), and others (16)(17)(18)), however, these studies reported low brain uptake, interaction with efflux transporters, or significant lack of specific binding in vivo. The OX1R-selective PET ligand candidates investigated so far faced the same challenges (Figure 1B), such that [ 18 F]THIQ derivatives showed low brain uptake due to poor pharmacokinetics (19), and [ 18 F]PBC-1 showed in vivo instability (20).…”

Section: Introductionmentioning

confidence: 99%

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Heteroaryl derivatives of suvorexant as OX1R selective PET ligand candidates: Cu-mediated 18F-fluorination of boroxines, in vitro and initial in vivo evaluation

Bolik,

Hellmann,

Maschauer

et al. 2024

Preprint

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Background: The orexin receptor (OXR) plays a role in drug addiction and appears as a tumor marker in colon carcinoma. Subtype-selective OXR PET ligands have not yet been reported. The present work deals with the development of 18F-labeled OXR ligands dervived from selective OX1R antagonist JH112. Methods: Applying computational analysis, medicinal chemistry, integrated OXR binding studies, Cu-mediated 18F-fluorination and initial small animal PET studies, we evaluated a series of OXR ligands (1a-1f), varying the heteroarene scaffold of FH112 by 5-fluorobenzoxazole, 5-/6-fluorobenzthiazole and 6-fluoroquinoxaline. Receptor binding studies were preformed on HEK293T cells transiently expressing the OX1R and OX2R. Cu-mediated 18F-fluorination was performed on BPin and boroxine precursors. In vitro assays for logD7.4, stability in plasma, plasma-protein binding and potential P-gp-mediated transport in the Caco-2 monolayer model were performed. The brain uptake of 18F-labeled ligands was studied by dynamic PET imaging in rats. Results: Computational analysis predicted that fluorine substitution (1e) and introduction of the fluorobenzothiazole scaffold (1f) would be suitable for maintaining high OX1R affinity. After multi-step synthesis of 1a-1f, in vitro OXR binding studies confirmed molecular dynamics calculations and revealed single-digit nanomolar OX1R affinities for 1a-f, ranging from 0.69 nM-2.5 nM. The benzothiazole 1f showed high OX1R affinity (Ki = 0.69 nM), along with 77-fold subtype selectivity over OX2R. Cu-mediated 18F-fluorination of the nonselective OXR ligands benzothiazole [18F]1c and quinoxaline [18F]1d yielded RCY of 44% and 56%, respectively, after 10 min, compared to low RCY for benzoxazole [18F]1a of 12% after 20 min. The nonselective OXR ligand [18F]1c and the selective OX1R ligand [18F]1f gave total activity yields of 14% and 22%, respectively, using boroxine precursors for Cu-mediated 18F-fluorination with 5 min reaction time and a total synthesis time of 50-60 min. [18F]1c and [18F]1f were stable in plasma and serum in vitro, with logD7.4 of 2.28 ([18F]1c) and 2.37 ([18F]1f), and high plasma-protein binding of 66% and 77%, respectively, reflecting only marginal differences in brain uptake of [18F]1c (0.17 %ID/g) and [18F]1f (0.15 %ID/g). 1c showed higher passive permeability than 1f in vitro, which was consistent with the faster brain clearance of [18F]1c compared to [18F]1f. However, preinjection of the OXR antagonist suvorexant did not significantly block [18F]1c or [18F]1f uptake in the rat brain. Pretreatment with cyclosporin A to study the role of P-gp in limiting brain accumulation moderately increased brain uptake of [18F]1c and [18F]1f. Accordingly, in vitro experiments demonstrated that the P-gp inhibitor zosuquidar only moderately inhibited polarized, basal to apical transport of 1c (p<0.05) and had no influence on transport of 1f (n.s.), indicating that P-gp does not play a relevant role in brain accumulation of [18F]1c and [18F]1f in vivo. Conclusions: The in vitro and in vivo results of [18F]1c and [18F]1f provide a solid basis for further development of suitable OXR PET ligands for brain imaging. This could be achieved through structural changes that would result in lower blood protein binding and 18F labeling methods that would allow for improved molar activities.

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Section: Figure 1 Overview Of Oxr Ligands Amentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Heteroaryl derivatives of suvorexant as OX1R selective PET ligand candidates: Cu-mediated 18F-fluorination of boroxines, in vitro and initial in vivo evaluation

Bolik,

Hellmann,

Maschauer

et al. 2024

Preprint

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“…Therefore, further modifications to improve the pharmacokinetic parameters would be needed. 122 Generally, the numerous OX-R radiotracers developed over the years presented several limitations, including specificity and brain permeability, which prevented their development as PET agents. Therefore, further efforts are still needed to build subtype-selective OX-R radiolabeled compounds with improved binding specificity and/or pharmacokinetic profiles, to be used as PET probes for imaging of OX1-R and OX2-R in the brain.…”

Section: Ox-r Ligands For Molecular Imagingmentioning

confidence: 99%

“…In particular, the selective agent [ 18 F]PBC‐1 (Figure 31) displayed good brain uptake in normal mice, but proved to be unstable in vivo. Therefore, further modifications to improve the pharmacokinetic parameters would be needed 122 …”

Section: Newly Developed Ox‐r Ligandsmentioning

confidence: 99%

Targeting orexin receptors: Recent advances in the development of subtype selective or dual ligands for the treatment of neuropsychiatric disorders

Bonifazi

Bello

Giorgioni

et al. 2023

Medicinal Research Reviews

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Orexin‐A and orexin‐B, also named hypocretin‐1 and hypocretin‐2, are two hypothalamic neuropeptides highly conserved across mammalian species. Their effects are mediated by two distinct G protein‐coupled receptors, namely orexin receptor type 1 (OX1‐R) and type 2 (OX2‐R), which share 64% amino acid identity. Given the wide expression of OX‐Rs in different central nervous system and peripheral areas and the several pathophysiological functions in which they are involved, including sleep‐wake cycle regulation (mainly mediated by OX2‐R), emotion, panic‐like behaviors, anxiety/stress, food intake, and energy homeostasis (mainly mediated by OX1‐R), both subtypes represent targets of interest for many structure–activity relationship (SAR) campaigns carried out by pharmaceutical companies and academies. However, before 2017 the research was predominantly directed towards dual‐orexin ligands, and limited chemotypes were investigated. Analytical characterizations, including resolved structures for both OX1‐R and OX2‐R in complex with agonists and antagonists, have improved the understanding of the molecular basis of receptor recognition and are assets for medicinal chemists in the design of subtype‐selective ligands. This review is focused on the medicinal chemistry aspects of small molecules acting as dual or subtype selective OX1‐R/OX2‐R agonists and antagonists belonging to different chemotypes and developed in the last years, including radiolabeled OX‐R ligands for molecular imaging. Moreover, the pharmacological effects of the most studied ligands in different neuropsychiatric diseases, such as sleep, mood, substance use, and eating disorders, as well as pain, have been discussed. Poly‐pharmacology applications and multitarget ligands have also been considered.

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“…However, these PET ligand candidates exhibited low brain uptake or high non-specific binding. Efforts to develop OX1R selective PET ligands (Figure 1) have faced equal challenges, such that [ 18 F]THIQ-1 and [ 18 F]THIQ-2 17 displayed low brain uptake, [ 18 F]PBC-1 18 exhibited unfavorable pharmacokinetic properties and [ 11 C]CW24 19 showed high non-specific binding in the brain.…”

Section: Introductionmentioning

confidence: 99%

Structure-guided discovery of orexin receptor-binding PET ligands

Distler,

Maschauer,

Neu

et al. 2024

Preprint

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Molecular imaging using positron emission tomography (PET) can serve as a promising tool for visualizing biological targets in the brain. Insights into the expression pattern and the in vivo imaging of the G protein-coupled orexin receptors OX1R and OX2R will further our understanding of the orexin system and its role in various physiological and pathophysiological processes. Guided by crystal structures of our lead compound JH112 and the approved hypnotic drug suvorexant bound to OX1R and OX2R, respectively, we herein describe the design and synthesis of two novel radioligands, [18F]KD23 and [18F]KD10. Key to the success of our structural modifications was a bioisosteric replacement of the triazole moiety with a fluorophenyl group. The 19F-substituted analog KD23 showed high affinity for the OX1R and selectivity over OX2R, while the high affinity ligand KD10 displayed similar Ki values for both subtypes. Radiolabeling starting from the respective pinacol ester precursors resulted in excellent radiochemical yields of 93% and 88% for [18F]KD23 and [18F]KD10, respectively, within 20 minutes. The new compounds will be useful in PET studies aimed at subtype-selective imaging of orexin receptors in brain tissue.

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Synthesis and biological evaluation of novel 18F-labeled phenylbenzofuran-2-carboxamide derivative for detection of orexin 1 receptor in the brain

Cited by 6 publications

References 22 publications

Heteroaryl derivatives of suvorexant as OX1R selective PET ligand candidates: Cu-mediated 18F-fluorination of boroxines, in vitro and initial in vivo evaluation

Heteroaryl derivatives of suvorexant as OX1R selective PET ligand candidates: Cu-mediated 18F-fluorination of boroxines, in vitro and initial in vivo evaluation

Targeting orexin receptors: Recent advances in the development of subtype selective or dual ligands for the treatment of neuropsychiatric disorders

Structure-guided discovery of orexin receptor-binding PET ligands

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