Synthesis and characterization of a new Carbon-11 labeled positron emission tomography radiotracer for RIPK1 neuroimaging

Computers in Biology and Medicine, Год журнала: 2025, Номер 192, С. 110324 - 110324

Опубликована: Май 8, 2025

Язык: Английский

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Structure-guided discovery of orexin receptor-binding PET ligands

Bioorganic & Medicinal Chemistry, Год журнала: 2024, Номер 110, С. 117823 - 117823

Опубликована: Июнь 28, 2024

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

Язык: Английский

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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

Опубликована: Май 20, 2024

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

Язык: Английский

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Development and Evaluation of [¹¹C]I-58: A Novel PET Radiotracer Targeting BRD4 BD2 for Advanced Epigenetic Imaging

ACS Omega, Год журнала: 2024, Номер unknown

Опубликована: Авг. 12, 2024

The paired bromodomains (BD1 and BD2), located in the bromodomain extra-terminal (BET) family proteins, perform specific functions gene transcriptional control expression. Targeting with inhibitors holds promise for achieving therapeutic benefits reduced side effects. However, comprehension of this target related to disease is still restricted. Positron emission tomography (PET) imaging a powerful tool that provides valuable avenue exploring BD2 bromodomain. This investigation introduces novel radioligand, [11C]I-58, PET targeting BET domain. synthesis compound I-58, along its radiosynthetic process C11 labeling, detailed, suitability [11C]I-58 evaluated. Initial study findings mice indicate exhibits suitable biodistribution peripheral organs tissues. Additionally, vitro autoradiography studies blocking experiments provide compelling evidence supporting binding These results establish as promising instrument research not only potential pave path developing radioligands precisely but also adds more profound biological mechanisms linked BD

Язык: Английский

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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

EJNMMI Research, Год журнала: 2024, Номер 14(1)

Опубликована: Сен. 4, 2024

Abstract Background The orexin receptor (OXR) plays a role in drug addiction and is aberrantly expressed colorectal tumors. Subtype-selective OXR PET ligands suitable for vivo use have not yet been reported. This work reports the development of 18 F-labeled ligand candidates derived from antagonist suvorexant OX1R-selective JH112. Results Computational analysis predicted that fluorine substitution (1e) introduction fluorobenzothiazole scaffold (1f) would be maintaining high OX1R affinity. After multi-step synthesis 1a–1f, vitro binding studies confirmed molecular dynamics calculations revealed single-digit nanomolar affinities 1a–f, ranging 0.69 to 2.5 nM. benzothiazole 1f showed affinity (K i = nM), along with 77-fold subtype selectivity over OX2R. Cu-mediated F-fluorination boroxine precursors allowed shortened reaction time 5 min provide non-selective [ F]1c its selective congener F]1f activity yields 14% 22%, respectively, within total 52–76 min. were stable plasma serum vitro, logD 7.4 2.28 ([ F]1c) 2.37 F]1f), protein 66% 77%, respectively. Dynamic imaging rats similar brain uptake (0.17%ID/g) (0.15%ID/g). However, preinjection did significantly block or rat brain. Pretreatment cyclosporine A study P-glycoprotein (P-gp) limiting accumulation moderately increased F]1f. Accordingly, experiments demonstrated P-gp inhibitor zosuquidar only inhibited polarized, basal apical transport 1c (p < 0.05) had no effect on 1f, indicating does play relevant vivo. Conclusions results solid basis further imaging.

Язык: Английский

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The Development and Evaluation of a Novel Highly Selective PET Radiotracer for Targeting BET BD1

Pharmaceuticals, Год журнала: 2024, Номер 17(10), С. 1289 - 1289

Опубликована: Сен. 27, 2024

Small molecules that interfere with the interaction between acetylated protein tails and tandem bromodomains of BET (bromodomain extra-terminal) family proteins are pivotal in modulating immune/inflammatory neoplastic diseases. This study aimed to develop a novel PET imaging tracer, [

Язык: Английский

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68Ga labeled Olmutinib: Design, synthesis, and evaluation of a novel PET EGFR probe

Bioorganic Chemistry, Год журнала: 2024, Номер 153, С. 107987 - 107987

Опубликована: Ноя. 21, 2024

Язык: Английский

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