Synthesis and characterization of a new Positron emission tomography probe for orexin 2 receptors neuroimaging

Bai, Ping; Liu, Yan; Xu, Yulong; Striar, Robin; Yuan, Gengyang; Afshar, Sepideh; Langan, Amelia G.; Rattray, A; Wang, Changning

doi:10.1016/j.bioorg.2022.105779

Cited by 8 publications

(30 citation statements)

References 32 publications

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“…[ 18 F]seltorexant (Figure 31) demonstrated strong binding specificity in ex vivo autoradiography studies, and showed suitable brain uptake in rodents, which further increased in the presence of the P‐gp competitor cyclosporin A (CsA), indicating that this compound is a P‐gp substrate. These findings are consequential for the development of novel OX2‐R PET radiotracers, which will help to further investigate the orexin system 120 …”

Section: Newly Developed Ox‐r Ligandsmentioning

confidence: 98%

“…These findings are consequential for the development of novel OX2-R PET radiotracers, which will help to further investigate the orexin system. 120 Concerning OX1-R, the first PET radiotracers were developed in 2019. Specifically, the selective OX1-R tetrahydroisoquinoline derivatives THIQ-1 and THIQ-2, bearing a fluoroethoxy substituent in para position of the benzyl group in position 1 or in position 7 of the tetrahydroisoquinoline moiety, respectively, were labeled with 18 F. Both PET imaging agents [ 18 F]THIQ-1 and [ 18 F]THIQ-2 (Figure 31) specifically bound to the OX1-R in vitro.…”

Section: Ox-r Ligands For Molecular Imagingmentioning

confidence: 99%

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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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Section: Newly Developed Ox‐r Ligandsmentioning

confidence: 98%

Section: Ox-r Ligands For Molecular Imagingmentioning

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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“…9,10) Since non-invasive imaging of OX 2 R could be useful for not only elucidation of orexin systems but also development of agonists/antagonists, several PET probes targeting OX 2 R have been developed. [11][12][13][14][15][16][17] First, 11 C-labeled probes, such as [ 11 C] EMPA, [ 11 C] BBAC, and [ 11 C] CW4, were reported, but these showed insufficient brain uptake or high non-specific accumulation in the brain for in vivo imaging. More recently, two 18 F-labeled probes, [ 18 F] DAN-1 and [ 18 F] seltorexant, were also reported.…”

Section: Introductionmentioning

confidence: 99%

“…16) [ 18 F] Seltorexant also penetrates the blood-brain barrier, but since it functions as a substrate of P-glycoprotein, an increase in brain uptake was observed in an in vivo blocking study. 17) Taken together, no promising probes for in vivo imaging of OX 2 R have been developed so far.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Characterization of Novel Radioiodinated Triazole-Pyrolidine Derivative to Detect Orexin 2 Receptor in the Brain

Watanabe

Ide

Ono

2023

CHEMICAL & PHARMACEUTICAL BULLETIN

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It is generally accepted that the orexin 2 receptor (OX 2 R) plays a critical role in the arousal-promoting function, and in vivo imaging of OX 2 R is expected to contribute to elucidation of orexin systems and the development of drugs to treat sleep disorder. In this study, we newly synthesized and characterized a radioiodinated triazole-pyrolidine derivative ([ 125 I]TPI) to detect OX 2 R in the brain. In vitro studies using OX 1 R or OX 2 R expression cells showed selective binding of [ 125 I]TPI to OX 2 R. In addition, in vitro autoradiography using rat brain sections showed high accumulation of radioactivity in the OX 2 R expression region. However, [ 125 I]TPI showed low brain uptake in normal mice. These results suggest that [ 125 I]TPI has a fundamental character to detect OX 2 R in vitro, but further structural modification to improve brain pharmacokinetics is required to use it for in vivo detection of OX 2 R.

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“…compared to low RCY for benzoxazole [ 18 F]1a of 12% after 20 min. The nonselective OXR ligand [ 18 F]1c and the selective OX1R ligand [ 18 F]1f gave total activity yields of 14% and 22%, respectively, using boroxine precursors for Cu-mediated 18 F-fluorination with 5 min reaction time and a total synthesis time of 50-60 min. [ 18 F]1c and [ 18 F]1f were stable in plasma and serum in vitro, with logD7.4 of 2.28 ([ 18 F]1c) and 2.37 ([ 18 F]1f), and high plasma-protein binding of 66% and 77%, respectively, reflecting only marginal differences in brain uptake of [ 18 F]1c (0.17 %ID/g) and [ 18 F]1f (0.15 %ID/g).…”

mentioning

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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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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Synthesis and characterization of a new Positron emission tomography probe for orexin 2 receptors neuroimaging

Cited by 8 publications

References 32 publications

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

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

Synthesis and Characterization of Novel Radioiodinated Triazole-Pyrolidine Derivative to Detect Orexin 2 Receptor in the Brain

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

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