Development of a novel fluorine-18 labeled deuterated fluororasagiline ([18F]fluororasagiline-D2) radioligand for PET studies of monoamino oxidase B (MAO-B)

Nag, Sangram; Lehmann, Lutz; Kettschau, Georg; Tóth, Miklós; Heinrich, Tobias; Thiele, Andrea; Varrone, Andrea; Halldin, Christer

doi:10.1016/j.bmc.2013.08.019

Cited by 44 publications

(29 citation statements)

References 22 publications

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“…[49] Aside from P450, other human metabolic enzymes,s uch as the aldehyde oxidase (AO) [50] and the monoamine oxidase (MAO) family, [51] also produce measurable KIEs.This effect is utilized for the quantification of native MAOe nzyme activities,f or example,inrelation to smoking,byadual tracer approach to compare the binding rates of selective PET radiotracers in the presence and absence of an additional deuterium label. [52] Depending on the enzymes involved, and hence the mechanism of the rate-determining step,a nother consequence can be ad ifferent metabolic turnover of ad rug molecule when replacing hydrogen for deuterium. [53] Although, in principle,t his has been known for many years, [54] the alteration of ADME properties by selective deuterium incorporation has only recently received more attention, [55] largely because an umber of companies have developed business models based on patenting and developing deuterated versions of existing therapeutic molecules.…”

Section: Isotope Effects For the Determination Of Enzyme Mechanismsmentioning

confidence: 99%

Deuterium‐ and Tritium‐Labelled Compounds: Applications in the Life Sciences

Atzrodt¹,

Derdau²,

et al. 2018

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Hydrogen isotopes are unique tools for identifying and understanding biological and chemical processes. Hydrogen isotope labelling allows for the traceless and direct incorporation of an additional mass or radioactive tag into an organic molecule with almost no changes in its chemical structure, physical properties, or biological activity. Using deuterium-labelled isotopologues to study the unique mass-spectrometric patterns generated from mixtures of biologically relevant molecules drastically simplifies analysis. Such methods are now providing unprecedented levels of insight in a wide and continuously growing range of applications in the life sciences and beyond. Tritium ( H), in particular, has seen an increase in utilization, especially in pharmaceutical drug discovery. The efforts and costs associated with the synthesis of labelled compounds are more than compensated for by the enhanced molecular sensitivity during analysis and the high reliability of the data obtained. In this Review, advances in the application of hydrogen isotopes in the life sciences are described.

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Section: Isotope Effects For the Determination Of Enzyme Mechanismsmentioning

confidence: 99%

Deuterium‐ and Tritium‐Labelled Compounds: Applications in the Life Sciences

Atzrodt¹,

Derdau²,

et al. 2018

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“…Although [ 11 C]L‐deprenyl‐D 2 has been widely used as a PET probe for MAO‐B imaging in clinical settings, the development of an 18 F‐labeled probe with a longer half‐life would be beneficial to increase the availability of MAO‐B imaging for patients. Recently, several 18 F‐labeled probes based on the structure of L‐deprenyl and rasagiline were imaged successfully in vivo in cynomolgus monkey brains . Thus, in this study, we aimed to develop a novel radiofluorinated probe based on the findings of 2‐[ 125 I]IBPO with the higher MAO‐B selectivity of 2‐IBPO and MD‐230254 in comparison with L‐deprenyl for PET imaging of such MAO‐B‐associated brain diseases.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and characterization of novel radiofluorinated probes for positron emission tomography imaging of monoamine oxidase B

Yoshimoto

Hirata

Kagawa

et al. 2019

Labelled Comp Radiopharmac

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Monoamine oxidase B (MAO-B), predominantly expressed in glial cells, plays an important role in neurotransmitter regulation, and MAO-B activity relates to several neuronal diseases. Here, we aimed to develop a radiofluorinated MAO-B imaging probe based on the structure of a selective MAO-B inhibitor, MD-230254. We synthesized and evaluated a series of compounds in vitro and in vivo. A series of fluorinated analogs of MD-230254 were synthesized and evaluated for inhibitory potency and selectivity toward MAO-B. 5-[4-(2-[ 18 F]Fluorobenzyloxy)phenyl]-3-(2-cyanoethyl)-1,3,4-oxadiazol-2(3H)-one (2-[ 18 F]FBPO) was synthesized from a corresponding tributylstannyl precursor and [ 18 F]CH 3 COOF. Biodistribution after intravenous injection of 2-[ 18 F]FBPO was evaluated in male ddY mice with or without pretreatment by inhibitors.Among the compounds synthesized and evaluated, 2-FBPO showed high inhibitory potency and selectivity toward MAO-B comparable with MD-230254. 2-[ 18 F]FBPO was successfully synthesized by an electrophilic reaction with a high radiochemical purity of more than 99%. 2-[ 18 F]FBPO was efficiently taken up by the brain and showed rapid blood clearance, which provided a brain/blood radioactivity ratio of 3.7 at 90 minutes postinjection. The brain radioactivity was significantly decreased by pretreatment with an MAO-B selective inhibitor. The great potential of 2-[ 18 F]FBPO as an MAO-B imaging probe, applicable to a variety of diseases, is indicated. KEYWORDS MAO, MAO-B, MD-230254, monoamine oxidase, positron emission tomography, PET, SPECT Mitsuyoshi Yoshimoto and Masahiko Hirata contributed equally to this manuscript.

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“…Such a radioligand might be a useful imaging tool for the detection of activated astrocytes in central nervous system disorders such as Alzheimer disease, Parkinson disease, and epilepsy. In our recent publications, we have reported several 18 F-labeled radiotracers such as 18 (25), and 18 F-fluororasagiline-D 2 (26).…”

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confidence: 99%

In Vivo and In Vitro Characterization of a Novel MAO-B Inhibitor Radioligand, ¹⁸F-Labeled Deuterated Fluorodeprenyl

et al. 2015

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The aim of this study was to radiolabel a novel bis-deuterium substituted L-deprenyl analog (fluorodeprenyl-D 2 ) with 18 F and to evaluate its potential to visualize and quantify monoamine oxidase (MAO) B activity in vivo. Methods: The precursor compound (5a 1 5b) and reference standard (6) were synthesized in multistep syntheses. Recombinant human MAO-B and MAO-A enzyme preparations were used to determine inhibitory concentrations of 50%. Radiolabeling was accomplished by a nucleophilic substitution reaction. Whole-hemisphere autoradiography was performed with 18 F-fluorodeprenyl-D 2 . A PET study was performed on a cynomolgus monkey. Radiometabolites were measured in monkey plasma using high-performance liquid chromatography. Results: The 50% inhibitory concentration of compound 6 for MAO-B was 227 ± 36.8 nM. Radiolabeling was accomplished with high radiochemical yield, purity, and specific radioactivity. The autoradiography binding density of 18 F-fluorodeprenyl-D 2 was consistent with known MAO-B expression in the human brain. In vivo, 18 F-fluorodeprenyl-D 2 showed favorable kinetic properties, with relatively fast washout from the brain. Regional time-activity curves were better described by the 2-tissuecompartment model. Administration of a 1 mg/kg dose of L-deprenyl yielded 70% inhibition of MAO-B in all regions. Radiometabolite studies demonstrated 20% unchanged radioligand at 120 min after injection. 18 F-fluorodeprenyl-D 2 showed less irreversibility than did previously reported MAO-B radioligands. Conclusion: The results suggest that 18 F-fluorodeprenyl-D 2 is a suitable PET radioligand for visualization of MAO-B activity in the human brain.

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Development of a novel fluorine-18 labeled deuterated fluororasagiline ([18F]fluororasagiline-D2) radioligand for PET studies of monoamino oxidase B (MAO-B)

Cited by 44 publications

References 22 publications

Deuterium‐ and Tritium‐Labelled Compounds: Applications in the Life Sciences

Deuterium‐ and Tritium‐Labelled Compounds: Applications in the Life Sciences

Synthesis and characterization of novel radiofluorinated probes for positron emission tomography imaging of monoamine oxidase B

In Vivo and In Vitro Characterization of a Novel MAO-B Inhibitor Radioligand, ¹⁸F-Labeled Deuterated Fluorodeprenyl

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Development of a novel fluorine-18 labeled deuterated fluororasagiline ([18F]fluororasagiline-D2) radioligand for PET studies of monoamino oxidase B (MAO-B)

Cited by 44 publications

References 22 publications

Deuterium‐ and Tritium‐Labelled Compounds: Applications in the Life Sciences

Deuterium‐ and Tritium‐Labelled Compounds: Applications in the Life Sciences

Synthesis and characterization of novel radiofluorinated probes for positron emission tomography imaging of monoamine oxidase B

In Vivo and In Vitro Characterization of a Novel MAO-B Inhibitor Radioligand, 18F-Labeled Deuterated Fluorodeprenyl

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In Vivo and In Vitro Characterization of a Novel MAO-B Inhibitor Radioligand, ¹⁸F-Labeled Deuterated Fluorodeprenyl