Preparation of highly specific radioactivity [18F]flumazenil and its evaluation in cynomolgus monkey by positron emission tomography

Ryzhikov, Nikolaj N.; Seneca, Nicholas; Красикова, Р. Н.; Gomzina, N. A.; Shchukin, Evgeny; Федорова, О. С.; Vassiliev, Dmitrij A.; Gulyás, Balázs; Hall, Håkan; Savić, Ivanka; Halldin, Christer

doi:10.1016/j.nucmedbio.2004.11.001

Cited by 72 publications

(38 citation statements)

References 21 publications

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“…A lowdose coacquired CT scan was used for attenuation correction. 18 F-FMZ was prepared according to the method described by Ryzhikov et al (13). Radiochemical purity was greater than 99%, and specific activity ranged from 125.06 to 480.63 GBq/mmol at the end of synthesis.…”

Section: Pet Imagingmentioning

confidence: 99%

¹⁸F-Flumazenil: A γ-Aminobutyric Acid A–Specific PET Radiotracer for the Localization of Drug-Resistant Temporal Lobe Epilepsy

et al. 2013

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Studies report that 11 C-flumazenil (FMZ) PET more specifically localizes the epileptogenic zone in patients with medically refractory focal epilepsy than 18 F-FDG PET. However, practical aspects of 11 C use limit clinical application. We report a phase I/IIa study assessing the clinical use of 18 F-FMZ PET for the localization of the epileptogenic zone in patients with drug-resistant temporal lobe epilepsy (TLE). Receptor binding was quantified using kinetic modeling that did not require arterial sampling. Methods: Dynamic 18 F-FMZ PET and static interictal 18 F-FDG PET scans were compared in healthy controls (n 5 17 for 18 F-FMZ and n 5 20 for 18 F-FDG) and TLE patients with mesial temporal sclerosis on MR imaging (MTS, n 5 12) and with normal MR imaging (NL TLE, n 5 19). Masked visual assessment of images was undertaken. Parametric images of 18 F-FMZ binding potential (BP ND ) were generated using the simplified reference tissue model. Region-of-interest analysis on coregistered MR images and statistical parametric mapping were used to quantify 18 F-FMZ BP ND and 18 F-FDG uptake in the temporal lobe. Results: The visual assessment of static standardized uptake value images showed 18 F-FMZ PET to have high specificity (16/17 [94%]) and moderate sensitivity (21/31 [68%]) for the localization of the epileptogenic zone, with a more restricted abnormality than 18 F-FDG PET. However, the 18 F-FMZ standardized uptake value images were falsely localizing in 3 of 31 patients (10%). Region-of-interest analysis demonstrated reductions in ipsilateral hippocampal 18 F-FMZ BP ND in patients with either MTS or NL TLE, compared with controls subjects. Ipsilateral hippocampal 18 F-FMZ BP ND was independent of both hippocampal volume and 18 F-FDG uptake, whereas ipsilateral hippocampal volume was correlated with 18 F-FDG uptake (r 2 5 0.69, P , 0.0001). Statistical parametric mapping analysis demonstrated decreased uptake in 14 of 31 (45%) cases with 18 F-FMZ PET and 18 of 29 (62%) with 18 F-FDG PET. Cluster size was significantly smaller on 18 F-FMZ than 18 F-FDG images (37 vs. 160 voxels, P , 0.01). Conclusion: 18 F-FMZ PET has potential as a clinical tool for the localization of the epileptogenic zone in the presurgical evaluation of drug-resistant TLE, providing information complementary to 18 F-FDG PET, with a more restricted region of abnormality.

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Section: Pet Imagingmentioning

confidence: 99%

¹⁸F-Flumazenil: A γ-Aminobutyric Acid A–Specific PET Radiotracer for the Localization of Drug-Resistant Temporal Lobe Epilepsy

et al. 2013

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“…No-carrier-added 18 F-LBT-999 was synthesized in a manner similar to previously described procedures (10,14). In short, 18 F-LBT-999 was produced via direct nucleophilic substitution of chloro analog Cl-LBT-999 by adding 1.5-2 mg of chloro precursor dissolved in 500 mL of dimethyl sulfoxide to the dry K 18 F/K(2.2.2) complex and heating the mixture at 165°C for 10 min.…”

Section: Preparation Of 18 F-lbt-999mentioning

confidence: 99%

Imaging of the Striatal and Extrastriatal Dopamine Transporter with ¹⁸F-LBT-999: Quantification, Biodistribution, and Radiation Dosimetry in Nonhuman Primates

Varrone¹,

Степанов²,

Nakao³

et al. 2011

J Nucl Med

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The aim of this study was to evaluate the quantification, biodistribution, and radiation dosimetry of the novel dopamine transporter (DAT) radioligand 18 F-(2S,3S)-methyl 8-((E)-4-fluorobut-2-en-1-yl)-3-(p-tolyl)-8-azabicyclo[3.2.1]octane-2-carboxylate ( 18 F-LBT-999) in nonhuman primates. Methods: The brain study was conducted in 4 female rhesus monkeys. PET measurements were conducted for 243 min using the high-resolution research tomograph (HRRT) with the measurement of the metabolite-corrected arterial input function and protein binding. Quantification was performed with kinetic analysis using 2-tissue-and 1-tissue-compartment models, with Logan graphical analysis and with different reference tissue models. The outcome measures were total distribution volume (V T ), nondisplaceable distribution volume (V ND ), binding potential relative to the free concentration of radioligand in plasma (BP F ), and binding potential relative to the concentration of nondisplaceable radioligand in tissue (BP ND ) 5 V T 2 V ND /V ND using the cerebellum as a reference region. For the biodistribution and radiation dosimetry, 2 female cynomolgus monkeys were studied. Whole-body PET scans were obtained using a PET/CT system for approximately 250 min. Estimates of the absorbed radiation dose in humans were calculated using OLINDA/EXM software. Results: 18 F-LBT-999 showed good brain uptake (300% standardized uptake value) and regional distribution according to known DAT density. The 2-tissuecompartment model was the preferred model for the quantification. Late peak equilibrium (120-140 min) and slow washout were observed in the striatum, with high variability of V T , BP F , and BP ND . When the different models were compared with the 2-tissuecompartment model, the underestimation of V T or BP ND was larger in the caudate and putamen than in the midbrain and thalamus. The reference tissue models were suitable for the quantification. The whole-body distribution study showed that the main routes of excretion of 18 F-LBT-999 were the urinary and gastrointestinal systems, with the bladder being the critical organ.Accumulation of 18 F-LBT-999 was found in the bone and skull, with a relatively high dose estimated for the osteogenic cells. The range of calculated effective dose was 0.021-0.022 mSv/MBq. Conclusion: 18 F-LBT-999 seemed to be a suitable PET radioligand for the DAT quantification, particularly for extrastriatal regions. The skull uptake did not seem to be a limitation for brain imaging. The calculated dosimetry estimates based on data in nonhuman primates seemed comparable with those of other clinically used 18 F-labeled radioligands, for example, 18 F-FDG (0.024-0.027 mSv/MBq). Dopami ne is one of the main monoamine neurotransmitters involved in the regulation of important brain functions, such as locomotor activity, reward, and cognition (1). The dopamine transporter (DAT) is the plasma membrane protein that acts by clearing dopamine released into the extracellular space. The highest density of the DAT protein is in the st...

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“…In addition, FMZ-binding was found to be decreased in patients with unilateral hippocampal sclerosis that is associated with neuron loss and hippocampal atrophy (Koepp et al, 1997) as well as in irreversibly damaged cortex already early after stroke (Heiss et al, 1998(Heiss et al, , 2001(Heiss et al, , 2004. Recently, the synthesis of 18 F-labelled flumazenil ([ 18 F]FMZ) was reported (Ryzhikov et al, 2005), the use of which is preferable to 11 C-labeled flumazenil ([ 11 C]FMZ) due to the longer half-time of the 18 F and the higher image quality in terms of spatial resolution due to the shorter positron range of 18 F as compared to 11 C. Therefore, the combined use of [ 18 F]FMZ and the dedicated highresolution brain PET scanner HRRT (Siemens Medical Solutions, Knoxville, TN, USA) may offer a PET image with the highest resolution available up to date (FWHM 2.3 mm) and enable an accurate assessment of cortical GABA A receptor density in-vivo.…”

Section: Introductionmentioning

confidence: 99%

Where in-vivo imaging meets cytoarchitectonics: The relationship between cortical thickness and neuronal density measured with high-resolution [18F]flumazenil-PET

et al. 2011

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Preparation of highly specific radioactivity [18F]flumazenil and its evaluation in cynomolgus monkey by positron emission tomography

Cited by 72 publications

References 21 publications

¹⁸F-Flumazenil: A γ-Aminobutyric Acid A–Specific PET Radiotracer for the Localization of Drug-Resistant Temporal Lobe Epilepsy

¹⁸F-Flumazenil: A γ-Aminobutyric Acid A–Specific PET Radiotracer for the Localization of Drug-Resistant Temporal Lobe Epilepsy

Imaging of the Striatal and Extrastriatal Dopamine Transporter with ¹⁸F-LBT-999: Quantification, Biodistribution, and Radiation Dosimetry in Nonhuman Primates

Where in-vivo imaging meets cytoarchitectonics: The relationship between cortical thickness and neuronal density measured with high-resolution [18F]flumazenil-PET

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Preparation of highly specific radioactivity [18F]flumazenil and its evaluation in cynomolgus monkey by positron emission tomography

Cited by 72 publications

References 21 publications

18F-Flumazenil: A γ-Aminobutyric Acid A–Specific PET Radiotracer for the Localization of Drug-Resistant Temporal Lobe Epilepsy

18F-Flumazenil: A γ-Aminobutyric Acid A–Specific PET Radiotracer for the Localization of Drug-Resistant Temporal Lobe Epilepsy

Imaging of the Striatal and Extrastriatal Dopamine Transporter with 18F-LBT-999: Quantification, Biodistribution, and Radiation Dosimetry in Nonhuman Primates

Where in-vivo imaging meets cytoarchitectonics: The relationship between cortical thickness and neuronal density measured with high-resolution [18F]flumazenil-PET

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About

¹⁸F-Flumazenil: A γ-Aminobutyric Acid A–Specific PET Radiotracer for the Localization of Drug-Resistant Temporal Lobe Epilepsy

¹⁸F-Flumazenil: A γ-Aminobutyric Acid A–Specific PET Radiotracer for the Localization of Drug-Resistant Temporal Lobe Epilepsy

Imaging of the Striatal and Extrastriatal Dopamine Transporter with ¹⁸F-LBT-999: Quantification, Biodistribution, and Radiation Dosimetry in Nonhuman Primates